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CalbindinD 28k immunohistochemistry on 100-μm cerebellar neocortex sections across all seven diagnoses. Several categories of morphologic changes in Purkinje cells are identified, including cell body loss, heterotopia (white arrow, d, f, g, l), dendrite swelling (white caret, c, e, h, l), and axonal changes including torpedoes (large black arrow, b-l), thickened axons (arrowhead, b, c, e, g-j), recurrent collaterals (black caret, b-l), terminal axonal sprouting (asterisk, e). a Normal appearance of Purkinje cell dendrites, cell bodies and thin axon profiles in the granule cell layer in cerebellar cortex of a control. b, c Mild Purkinje cell axonal changes are seen in dystonia (b) and Parkinson's (c), with sparse thickened axons, recurrent collaterals and a torpedo. A dendrite swelling is present (c). d, e In Essential tremor, morphologic changes are more prominent, with greater loss of Purkinje cell bodies, heterotopia (d), dendrite swelling (e), thickened axon (e), several recurrent collaterals and torpedoes (d, e) and terminal axonal sprouting (e). ( f) SCA3 with intermediate axonal
Source publication
Several morphological changes, centered in/around Purkinje cells (PCs), have been identified in the cerebellum of essential tremor (ET) patients. These changes have not been contextualized within a broader degenerative disease spectrum, limiting their interpretability. To address this, we compared the severity and patterning of degenerative changes...
Contexts in source publication
Context 1
... of these disease patterns across diagnostic categories are observed in calbindinD 28k immunostained cerebellar sections (Fig. 4). Changes in PC axonal shape (e.g., torpedoes, thickened axons) and connectivity (e.g., recurrent collaterals, axonal branching) and PC body loss were less apparent in dystonia and Parkinson's (Fig. 4b, c) than ET (Fig. 4d, e), and heterotopias and dendrite swellings were more frequent in ET. Despite the relative preservation of PCs in ...
Context 2
... of these disease patterns across diagnostic categories are observed in calbindinD 28k immunostained cerebellar sections (Fig. 4). Changes in PC axonal shape (e.g., torpedoes, thickened axons) and connectivity (e.g., recurrent collaterals, axonal branching) and PC body loss were less apparent in dystonia and Parkinson's (Fig. 4b, c) than ET (Fig. 4d, e), and heterotopias and dendrite swellings were more frequent in ET. Despite the relative preservation of PCs in SCA3, PC axonal changes and occasional heterotopic PCs are seen (Fig. 4f), along with dendrite swellings (not shown). Both SCA1/2/6 and MSA showed a wide range of PC loss, along with marked increases in PC ...
Context 3
... of these disease patterns across diagnostic categories are observed in calbindinD 28k immunostained cerebellar sections (Fig. 4). Changes in PC axonal shape (e.g., torpedoes, thickened axons) and connectivity (e.g., recurrent collaterals, axonal branching) and PC body loss were less apparent in dystonia and Parkinson's (Fig. 4b, c) than ET (Fig. 4d, e), and heterotopias and dendrite swellings were more frequent in ET. Despite the relative preservation of PCs in SCA3, PC axonal changes and occasional heterotopic PCs are seen (Fig. 4f), along with dendrite swellings (not shown). Both SCA1/2/6 and MSA showed a wide range of PC loss, along with marked increases in PC axonal changes ( ...
Context 4
... axons) and connectivity (e.g., recurrent collaterals, axonal branching) and PC body loss were less apparent in dystonia and Parkinson's (Fig. 4b, c) than ET (Fig. 4d, e), and heterotopias and dendrite swellings were more frequent in ET. Despite the relative preservation of PCs in SCA3, PC axonal changes and occasional heterotopic PCs are seen (Fig. 4f), along with dendrite swellings (not shown). Both SCA1/2/6 and MSA showed a wide range of PC loss, along with marked increases in PC axonal changes ( Fig. 4g-l). A more variable PC loss in MSA often resulted in quite abundant torpedo formation, with some PC axons extending into better-preserved white matter (Fig. 4j), whereas areas of ...
Context 5
... (Fig. 4d, e), and heterotopias and dendrite swellings were more frequent in ET. Despite the relative preservation of PCs in SCA3, PC axonal changes and occasional heterotopic PCs are seen (Fig. 4f), along with dendrite swellings (not shown). Both SCA1/2/6 and MSA showed a wide range of PC loss, along with marked increases in PC axonal changes ( Fig. 4g-l). A more variable PC loss in MSA often resulted in quite abundant torpedo formation, with some PC axons extending into better-preserved white matter (Fig. 4j), whereas areas of more severe white matter degeneration showed many torpedoes associated with prominent recurrent axons (Fig. 4k), indicating a greater disconnection of PCs from ...
Context 6
... heterotopic PCs are seen (Fig. 4f), along with dendrite swellings (not shown). Both SCA1/2/6 and MSA showed a wide range of PC loss, along with marked increases in PC axonal changes ( Fig. 4g-l). A more variable PC loss in MSA often resulted in quite abundant torpedo formation, with some PC axons extending into better-preserved white matter (Fig. 4j), whereas areas of more severe white matter degeneration showed many torpedoes associated with prominent recurrent axons (Fig. 4k), indicating a greater disconnection of PCs from their target cerebellar nuclei, perhaps replaced by reorganization of intracortical cerebellar ...
Context 7
... PC loss, along with marked increases in PC axonal changes ( Fig. 4g-l). A more variable PC loss in MSA often resulted in quite abundant torpedo formation, with some PC axons extending into better-preserved white matter (Fig. 4j), whereas areas of more severe white matter degeneration showed many torpedoes associated with prominent recurrent axons (Fig. 4k), indicating a greater disconnection of PCs from their target cerebellar nuclei, perhaps replaced by reorganization of intracortical cerebellar ...
Citations
... 6 From these studies, one can see evidence of an emerging underlying neuropathology in the ET cerebellar cortex. 7 These neuropathological studies have identified numerous degenerative changes centered in and around Purkinje cells (PCs), including the cell body (PC loss, 8,9 heterotopic PCs, and 10,11 empty PC basket plexus 12 ), PC dendrites (dendritic swellings, 13 reduction in branch complexity, and spine loss 14,15 ), PC axons (axonal swellings [torpedoes], 16,17 axon branching, 18 recurrent axon collaterals, 18 and thickened axon profiles 18 ), and synaptic connections with adjacent neuronal populations ("hairy" baskets involving changes in basket cell axonal morphology, 19 elongated LINGO1-labeled basket cell pinceau processes and increased cerebellar LINGO1 protein levels, 20,21 decreased climbing fiber synaptic density, 22 and increased climbing fiber extension into parallel fiber territory 23 ). A small body of additional papers also focus on the relationship between ET and Alzheimer's type changes. ...
... The ETCBR, which was established in 2003 and serves ET cases throughout the United States, is a longstanding, joint collaboration between investigators at University Texas Southwestern Medical Center and Columbia Universities. 7,11,18,28 ET diagnoses were assigned by a senior movement disorders neurologist specializing in tremor (E.D.L.), using three sequential methods, as has been our practice for 20 years, and as employed in over 50 publications. 7,8,11,14,18,28 First, the clinical diagnosis of ET was initially assigned by treating neurologist(s), and second, confirmed by E.D.L. who reviewed semi-structured clinical questionnaires, medical records, and Archimedes spirals and who used the following criteria: (i) moderate or greater amplitude kinetic tremor (i.e., a severity rating ≥2 29 ) in at least one of the submitted Archimedes spirals; (ii) no history of PD or dystonia; and (iii) no other etiology for tremor (e.g., medication-induced tremor and hyperthyroidism). ...
... 7,11,18,28 ET diagnoses were assigned by a senior movement disorders neurologist specializing in tremor (E.D.L.), using three sequential methods, as has been our practice for 20 years, and as employed in over 50 publications. 7,8,11,14,18,28 First, the clinical diagnosis of ET was initially assigned by treating neurologist(s), and second, confirmed by E.D.L. who reviewed semi-structured clinical questionnaires, medical records, and Archimedes spirals and who used the following criteria: (i) moderate or greater amplitude kinetic tremor (i.e., a severity rating ≥2 29 ) in at least one of the submitted Archimedes spirals; (ii) no history of PD or dystonia; and (iii) no other etiology for tremor (e.g., medication-induced tremor and hyperthyroidism). 7,11,18,28 Third, a detailed, videotaped, neurological examination was performed, from which action tremor was rated on numerous tasks (e.g., pouring, drinking, using a spoon, finger-nose-finger maneuver, and spiral drawing) and a total tremor score assigned (range = 0-36 [maximum]). ...
Objective
Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain studies, hindering attempts to develop pathologically based criteria to distinguish essential tremor from control brains. However, an intensive effort to bank essential tremor brains over recent years has resulted in postmortem studies involving >200 brains, which have identified numerous degenerative changes in the essential tremor cerebellar cortex. Although essential tremor and controls have been compared with respect to individual metrics of pathology, there has been no overarching analysis to derive a combination of metrics to distinguish essential tremor from controls. We asked whether there is a constellation of pathological findings that separates essential tremor from controls, and how well that constellation performs.
Methods
Analyses included 100 essential tremor brains from the essential tremor centralized brain repository and 50 control brains. A standard tissue block from the cerebellar cortex was used to quantify 11 metrics of pathological change. Three supervised classification algorithms were investigated, with data divided into training and validation samples.
Results
Using three different algorithms, we illustrate the ability to correctly predict a diagnosis of essential tremor, with sensitivity and specificity >87%, and in the majority of situations, >90%. We also provide a web‐based application that uses these metric values, and based on specified cutoffs, determines the likely diagnosis.
Interpretation
These analyses set the stage for use of pathologically based criteria to distinguish clinically diagnosed essential tremor cases from controls, at the time of postmortem.
... Moreover, both in vitro (Radman et al., 2009) and computational modeling studies (Zhang et al., 2021) have indicated that Purkinje cells, the predominant neuron type in the cerebellum, exhibit heightened sensitivity to tDCS. Intriguingly, varying degrees of Purkinje cell loss have been documented in distinct spinocerebellar ataxias (Louis et al., 2019), potentially influencing outcomes in trials employing tES protocols. ...
Background: Converging evidence points to impairments of the predictive function exerted by the cerebellum as
one of the causes of the social cognition deficits observed in patients with cerebellar disorders.
Objective: We tested the neurorestorative effects of cerebellar transcranial direct current stimulation (ctDCS) on
the use of contextual expectations to interpret actions occurring in ambiguous sensory sceneries in a sample of
adolescents and young adults with congenital, non-progressive cerebellar malformation (CM).
Methods: We administered an action prediction task in which, in an implicit-learning phase, the probability of cooccurrence
between actions and contextual elements was manipulated to form either strongly or moderately
informative expectations. Subsequently, in a testing phase, we probed the use of these contextual expectations for
predicting ambiguous (i.e., temporally occluded) actions. In a sham-controlled, within-subject design, participants
received anodic or sham ctDCS during the task.
Results: Anodic ctDCS, compared to sham, improved patients’ ability to use contextual expectations to predict the
unfolding of actions embedded in moderately, but not strongly, informative contexts.
Conclusions: These findings corroborate the role of the cerebellum in using previously learned contextual associations
to predict social events and document the efficacy of ctDCS to boost social prediction in patients with
congenital cerebellar malformation. The study encourages the further exploration of ctDCS as a neurorestorative
tool for the neurorehabilitation of social cognition abilities in neurological, neuropsychiatric, and neurodevelopmental
disorders featured by macro- or micro-structural alterations of the cerebellum.
... The phenotypes between different races and lineages can also be heterogeneous. Some overlapping cerebellar pathological changes have been found between ET and SCAs [6][7][8]. Although ataxia is the most characteristic clinical feature in SCAs, certain SCA subtypes could manifest tremor like ET [9][10][11]. ...
... Although two of our patients didn't show cerebellar changes in brain MR, the structural changes in the cerebellum have been identified in many post-mortem studies of ET and SCA [6,7,29,30]. Converging lines of evidence have supported the presence of the tremor-related brain network, which consists of brainstem nuclei, cerebellum, thalamus, and motor cortex. ...
... While the cascade dysfunction of calcium signaling related to CF, including metabotropic glutamate receptors (mGluRs) [36], inositol 1,4,5-trisphosphate receptor 1 (IP 3 R1) [37,38] have been found in SCA subtypes. It is presumed that there is a common pathway in the pathogenesis of ET and SCA, and the only distinguishing feature lies in the degree of changing patterns [7]. However, as the phenomenon of excessive CF-PC synapses by increasing number of CF synapses stretching to the PF synaptic territories is exclusively expressed in ET, we cannot conclude that ET patients are predisposed to develop SCA. ...
Background
Essential tremor (ET) is a neurological disease characterized by action tremor in upper arms. Although its high heritability and prevalence worldwide, its etiology and association with other diseases are still unknown.
Method
We investigated 10 common spinocerebellar ataxias (SCAs), including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA36, dentatorubral-pallidoluysian atrophy (DRPLA) in 92 early-onset familial ET pedigrees in China collected from 2016 to 2022.
Result
We found one SCA12 proband carried 51 CAG repeats within PPP2R2B gene and one SCA3 proband with intermediate CAG repeats (55) with ATXN3 gene. The other 90 ET probands all had normal repeat expansions.
Conclusion
Tremor can be the initial phenotype of certain SCA. For early-onset, familial ET patients, careful physical examinations are needed before genetic SCA screening.
... In the most recent study on 156 brains with ET, spinocerebellar ataxias, multiple system atrophy, Parkinson's disease, dystonia and controls, Louis et al. investigated the numbers of Purkinje cells, heterotopic Purkinje cells, Purkinje cells' dendritic and axonal changes, basket cell axonal changes, and climbing fibre to Purkinje cells synaptic changes between the groups of the study. They found that ET brains showed significant changes in most of the parameters compared to normal controls [39]. ...
... Purkinje cells' heterotopias with their cell's bodies mislocated in the molecular layer have also been reported by other studies, as a disease-associated feature of ET [26,39,40], and are also considered as markers of neurodegeneration. Kuo et al. on a post-mortem study (Table II). ...
... Purkinje cells' dendrites is another potential target for degeneration in patients with ET [39,41]. A study on cerebellar cortical tissue from 27 ET cases and 27 agematched controls using Golgi-Kopsch method, and quantitative estimation of Purkinje cell dendritic anatomy revealed a significant reduction in dendritic com-plexity in ET cases. ...
... An intensive effort to bank ET brains over the past 10 to 20 years has resulted in postmortem studies involving more than 200 brains [10]. From these studies, one sees emerging evidence of an underlying neuropathology [11]. As such, postmortem changes are centered in and around PCs, with numerous studies demonstrating PC loss as well as a host of additional changes [12][13][14]. ...
Objective
Despite being one of the most prevalent neurological diseases, the pathophysiology of essential tremor (ET) is not fully understood. Neuropathological studies have identified numerous degenerative changes in the cerebellum of ET patients, however. These data align with considerable clinical and neurophysiological data linking ET to the cerebellum. While neuroimaging studies have variably shown mild atrophy in the cerebellum, marked atrophy is not a clear feature of the cerebellum in ET and a search for a more suitable neuroimaging signature of neurodegeneration is in order. Postmortem studies in ET have examined different neuropathological alterations in the cerebellum, but as of yet have not focused on measures of generalized synaptic markers. This pilot study focuses on synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in practically all synapses in the brain, as a measure of synaptic density in postmortem ET cases.
Methods
The current study utilized autoradiography with the SV2A radioligand [¹⁸F]SDM-16 to assess synaptic density in the cerebellar cortex and dentate nucleus in three ET cases and three age-matched controls.
Results
Using [¹⁸F]SDM-16, SV2A was 53% and 46% lower in the cerebellar cortex and dentate nucleus, respectively, in ET cases compared to age-matched controls.
Conclusion
In this pilot study, using in vitro SV2A autoradiography, we have observed significantly lower synaptic density in the cerebellar cortex and dentate nucleus of ET cases. Future research could expand on our sample size and focus on in vivo imaging in ET to explore whether SV2A imaging could serve as a much-needed disease biomarker.
... Despite this high prevalence, the pathophysiology of ET is not completely understood, and there are limited therapeutic options. To shed light on the pathophysiology of ET, our lab has collected and cataloged the largest ET brain repository in the world, which has led to identification of a series of structural and molecular changes in the ET cerebellum [54]. ...
... Eighteen ET brains were obtained from the Essential Tremor Centralized Brain Repository (ETCBR), a longstanding collaboration between investigators at UT Southwestern and Columbia University [54]. These samples were chosen from a larger inventory of frozen samples used in recent sequencing studies and were selected so that for each decade of life, from 7 to 10th, there would be several analyzed samples. ...
... These samples were chosen from a larger inventory of frozen samples used in recent sequencing studies and were selected so that for each decade of life, from 7 to 10th, there would be several analyzed samples. ET diagnosis was confirmed by a senior movement disorder neurologist (EDL) using three sequential methods, as detailed previously [54]. No ET patients had a history of heavy ethanol use, traumatic brain injury or exposure to any medication known to cause cerebellar damage. ...
Essential Tremor (ET) is a prevalent neurological disease characterized by an 8–10 Hz action tremor. Molecular mechanisms of ET remain poorly understood. Clinical data suggest the importance of the cerebellum in disease pathophysiology, and pathological studies indicate Purkinje Cells (PCs) incur damage. Our recent cerebellar cortex and PC-specific transcriptome studies identified alterations in calcium (Ca²⁺) signaling pathways that included ryanodine receptor type 1 (RyR1) in ET. RyR1 is an intracellular Ca²⁺ release channel located on the Endoplasmic Reticulum (ER), and in cerebellum is predominantly expressed in PCs. Under stress conditions, RyR1 undergoes several post-translational modifications (protein kinase A [PKA] phosphorylation, oxidation, nitrosylation), coupled with depletion of the channel-stabilizing binding partner calstabin1, which collectively characterize a “leaky channel” biochemical signature. In this study, we found markedly increased PKA phosphorylation at the RyR1-S2844 site, increased RyR1 oxidation and nitrosylation, and calstabin1 depletion from the RyR1 complex in postmortem ET cerebellum. Decreased calstabin1-RyR1-binding affinity correlated with loss of PCs and climbing fiber-PC synapses in ET. This ‘leaky’ RyR1 signature was not seen in control or Parkinson’s disease cerebellum. Microsomes from postmortem cerebellum demonstrated excessive ER Ca²⁺ leak in ET vs. controls, attenuated by channel stabilization. We further studied the role of RyR1 in tremor using a mouse model harboring a RyR1 point mutation that mimics constitutive site-specific PKA phosphorylation (RyR1-S2844D). RyR1-S2844D homozygous mice develop a 10 Hz action tremor and robust abnormal oscillatory activity in cerebellar physiological recordings. Intra-cerebellar microinfusion of RyR1 agonist or antagonist, respectively, increased or decreased tremor amplitude in RyR1-S2844D mice, supporting a direct role of cerebellar RyR1 leakiness for tremor generation. Treating RyR1-S2844D mice with a novel RyR1 channel-stabilizing compound, Rycal, effectively dampened cerebellar oscillatory activity, suppressed tremor, and normalized cerebellar RyR1-calstabin1 binding. These data collectively support that stress-associated ER Ca²⁺ leak via RyR1 may contribute to tremor pathophysiology.
... Recently, studies have found that some ET patients got the wrong diagnosis because of the solo and mild symptom of tremor at the beginning [6][7][8][9][10] . Previous pathological studies have also found some overlaps in cerebellar changes between ET and other neurological diseases, such as spinocerebellar ataxias (SCAs) [11][12][13] . The correlation between the genotype and phenotype of SCAs remains ambiguous. ...
... Although two of our patients didn't show cerebellar changes in brain MR, the structural changes in the cerebellum have been identi ed in many post-mortem studies of ET and SCA [11,12,38,39] . Converging lines of evidence have supported the presence of the tremor-related brain network, which consists of brainstem nuclei, cerebellum, thalamus, and motor cortex. ...
... While the cascade dysfunction of calcium signaling related to CF, including metabotropic glutamate receptors (mGluRs) [47] , inositol 1,4,5-trisphosphate receptor 1 (IP 3 R1) [48,49] have been found in SCA subtypes. It is presumed that there is a common pathway in the pathogenesis of ET and SCA, and the only distinguishing feature lies in the degree of changing patterns [12] . However, as the phenomenon of excessive CF-PC synapses by increasing number of CF synapses stretching to the PF synaptic territories is exclusively expressed in ET, we cannot conclude that ET patients are predisposed to develop SCA. ...
Background
Essential tremor (ET) is a neurological disease characterized by action tremor in upper arms. Although its high heritability and prevalence worldwide, its etiology and association with other diseases are still unknown.
Method
We investigated 10 common spinocerebellar ataxias (SCAs), including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA36, dentatorubral-pallidoluysian atrophy (DRPLA) in 92 early-onset familial ET pedigrees in China collected from 2016 to 2022.
Result
We found one SCA12 proband carried 51 CAG repeats within PPP2R2B gene and one SCA3 proband with intermediate CAG repeats (55) with ATXN3 gene. The other 90 ET probands all had normal repeat expansions.
Conclusion
Tremor can be the initial phenotype of certain SCA and it is necessary to screen SCAs in ET patients, especially in early-onset and familial patients.
... However, over the past 10 to 20 years, an intensive effort to bank ET brains has resulted in postmortem studies involving more than 200 brains [33]. From these studies, one sees evidence of an emerging underlying neuropathology [34]. Postmortem changes are centered in and around Purkinje cells (PCs), with numerous studies demonstrating PC loss [16,32,36]. ...
Objective
Despite being one of the most prevalent neurological diseases, the pathophysiology of essential tremor (ET) is not fully understood. Neuropathological studies have identified numerous degenerative changes in the cerebellum of ET patients, however. These data align with considerable clinical and neurophysiological data linking ET to the cerebellum. While neuroimaging studies have variably shown mild atrophy in the cerebellum, marked atrophy is not a clear feature of the cerebellum in ET and that a search for a more suitable neuroimaging signature of neurodegeneration is in order. Postmortem studies in ET have examined different neuropathological alterations in the cerebellum, but as of yet have not focused on measures of generalized synaptic markers. This pilot study focuses on synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in practically all synapses in the brain, as a measure of synaptic density in postmortem ET cases.
Methods
The current study utilized autoradiography with the SV2A radioligand [¹⁸F]SDM-16 to assess synaptic density in the cerebellar cortex and dentate nucleus in three ET cases and three age-matched controls.
Results
Using [¹⁸F]SDM-16, SV2A was 53% and 46% lower in the cerebellar cortex and dentate nucleus, respectively, in ET cases compared to age-matched controls.
Conclusion
For the first time, using in vitro SV2A autoradiography, we have observed significantly lower synaptic density in the cerebellar cortex and dentate nucleus of ET cases. Future research could focus on in vivo imaging in ET to explore whether SV2A imaging could serve as a much-needed disease biomarker.
... Consistently, studies have found a selective reduction in the levels of EAAT2, but not EAAT1, in the postmortem ET cerebellar cortex [17,100], suggesting that hyper-excitability may contribute to PC degenerative changes in ET. Moreover, Bergmann glia, the main type of astrocyte in cerebellar cortex, shows gliosis in a subset of ET cases [101]. This may cause improper clearance of glutamate, which leads to neurotoxic effects of PCs, relieving the DCN of inhibitory tone and enhancing output that contributes to tremor. ...
... Many pathological features of ET fall within the neurodegenerative changes in the cerebellum. In a large study comparing ET with other prototypical cerebellar degenerative disorders, such as spinocerebellar ataxias and multiple system atrophy cerebellar type (i.e., ataxic disorders), ET has a milder degree of cerebellar degenerative changes compared to ataxic disorders [101]. Interestingly, distal and lateral extension of climbing fibers into parallel fiber synaptic territory appears to be one of the more specific findings in ET [98,101]. ...
... In a large study comparing ET with other prototypical cerebellar degenerative disorders, such as spinocerebellar ataxias and multiple system atrophy cerebellar type (i.e., ataxic disorders), ET has a milder degree of cerebellar degenerative changes compared to ataxic disorders [101]. Interestingly, distal and lateral extension of climbing fibers into parallel fiber synaptic territory appears to be one of the more specific findings in ET [98,101]. This suggests that dendritic integration and synchrony are altered, which may cause mistimed cerebellar output and contribute to tremor generation. ...
Essential tremor (ET) is a common movement disorder affecting millions of people. Studies of ET patients and perturbations in animal models have provided a foundation for the neural networks involved in its pathophysiology. However, ET encompasses a wide variability of phenotypic expression, and this may be the consequence of dysfunction in distinct subcircuits in the brain. The cerebello-thalamo-cortical circuit is a common substrate for the multiple subtypes of action tremor. Within the cerebellum, three sets of cerebellar cortex-deep cerebellar nuclei connections are important for tremor. The lateral hemispheres and dentate nuclei may be involved in intention, postural and isometric tremor. The intermediate zone and interposed nuclei could be involved in intention tremor. The vermis and fastigial nuclei could be involved in head and proximal upper extremity tremor. Studying distinct cerebellar circuitry will provide important framework for understanding the clinical heterogeneity of ET.
... The developmental peak of PCs occurs in the postnatal period in mice. A variety of diseases (e.g., spinocerebellar ataxia [5,6], idiopathic tremor [7,8], Huntington's disease [9] and Autism Spectrum Disorder [10]) are accompanied by PC degeneration, which is a key factor causing disordered cerebellar function. A variety of genes have been found to be involved in the maintenance of PC physiological function [11,12], but the precise molecular mechanisms underlying the development and survival of PCs are unclear. ...
Purkinje cells (PCs), as a unique type of neurons output from the cerebellar cortex, are essential for the development and physiological function of the cerebellum. However, the intricate mechanisms underlying the maintenance of Purkinje cells are unclear. The O-GlcNAcylation (O-GlcNAc) of proteins is an emerging regulator of brain function that maintains normal development and neuronal circuity. In this study, we demonstrate that the O-GlcNAc transferase (OGT) in PCs maintains the survival of PCs. Furthermore, a loss of OGT in PCs induces severe ataxia, extensor rigidity and posture abnormalities in mice. Mechanistically, OGT regulates the survival of PCs by inhibiting the generation of intracellular reactive oxygen species (ROS). These data reveal a critical role of O-GlcNAc signaling in the survival and maintenance of cerebellar PCs.
