Objective: This study was designed to determine the presence of common types of proteinopathies in the cerebellar cortex of patients who died with essential tremor (ET).

Background: ET is the most common movement disorders. Previous post mortem studies suggest that ET may involve a neurodegenerative process leading to a dysfunction of the cerebellum[1]. Virtually all neurodegenerative diseases involve at least one proteinopathy, characterized by abnormal accumulation and aggregation of proteins in the brain[2]. We previously reported an accumulation of β-amyloid in the cerebellum of a subset of patients with ET[3].

Method: Tau, TDP-43, FUS and α-synuclein were quantified using Western immunoblots in cerebellar cortex homogenates from Controls (n=19), PD patients (n=16) and ET patients (n=14), separated in TBS-soluble (cytosolic proteins), detergent-soluble (membrane proteins) and detergent-insoluble (aggregated proteins) fractions. A total of 7 monoclonal antibodies (mAbs) and 3 polyclonal antibodies (pAbs) were used.

Results: No statistically significant changes were detected in the cerebellar concentrations of total tau (mAbs: tau-13 and tau-5), phosphorylated tau (Ser396/404 and Thr212/Ser214, mAbs AD2 and AT100), TDP-43 (full length 2E2-D3 mAbs and C-terminal segment pAbs), phospho-TDP-43 (Ser409/410 pAbs), FUS (pAbs ), α-syn and phospho-α-syn (Ser129, mAbs MJF-R1 and MJF-R13) between each of the groups studied. However, important interindividual variations were found for proteins investigated within each group. Adjustment for sex, cerebellar pH, post-mortem interval and/or age at death did not change statistical significance. Linear regression analyzes between clinical variables and proteins were largely not significant. However, positive linear regressions were observed between LINGO-1 and detergent-soluble TDP-43 or TBS-soluble FUS.

Conclusion: The present data does not support the hypothesis that the pathogenesis of ET is associated with the frank development of classical forms of the proteinopathies in the cerebellar cortex.

References: [1] E. D. Louis et al., “Contextualizing the pathology in the essential tremor cerebellar cortex: a patholog-omics approach,” (in eng), Acta Neuropathol, vol. 138, no. 5, pp. 859-876, 11 2019, doi: 10.1007/s00401-019-02043-7. [2] T. A. Bayer, “Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?,” (in eng), Eur Neuropsychopharmacol, vol. 25, no. 5, pp. 713-24, May 2015, doi: 10.1016/j.euroneuro.2013.03.007. [3] E. Béliveau et al., “Accumulation of amyloid-β in the cerebellar cortex of essential tremor patients,” (in eng), Neurobiol Dis, vol. 82, pp. 397-408, Oct 2015, doi: 10.1016/j.nbd.2015.07.016.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/no-frank-biochemical-evidence-of-proteinopathy-in-the-cerebellar-cortex-of-patients-with-essential-tremor/