{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:47:05Z","timestamp":1782280025301,"version":"3.54.5"},"posted":{"date-parts":[[2025,1,28]]},"group-title":"Neuroscience","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T00:00:00Z","timestamp":1738022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>An enduring puzzle in many inherited neurological disorders is the late onset of symptoms despite expression of function-impairing mutant protein early in life. We examined the basis for onset of impairment in Spinocerebellar ataxia type 6 (SCA6), a canonical late-onset neurodegenerative ataxia which results from a polyglutamine expansion in the voltage gated calcium channel, Cav2.1. Cerebellar Purkinje cell spiking abnormalities are seen concurrent with motor impairment in SCA6 mice but the basis for these changes in spiking is unknown. We identify endoplasmic reticulum (ER) calcium depletion as the cause for Purkinje cell spiking abnormalities and that the impairments in Purkinje cell spiking are unrelated to Cav2.1 ion-flux function. Further, intact inhibitory neurotransmission in the cerebellar cortex is necessary for Purkinje neurons to exhibit spiking abnormalities in SCA6 mice. Based on serial cerebellar transcriptome analysis, we define a mechanism of disease that is related to ER stress. Further, our studies support a model whereby proteotoxicity from misfolded mutant Cav2.1 is mitigated by a HSP90-dependent unfolded protein response (UPR) and that age-related breakdown of this response causes motor dysfunction and aberrant Purkinje cell spiking. Redundant pathways of the UPR mediate this resilience to ER stress. These studies elucidate a mechanism of resilience connecting aberrant proteostasis and calcium-dependent intrinsic membrane hyperexcitability to explain delayed disease onset more widely in age-dependent neurodegenerative disease.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    Advancing age is the single most important risk factor for neurodegenerative disease. Understanding how age intersects with genetic risk is therefore a critical challenge for neurodegenerative disease research. SCA6, a canonical late-onset degenerative cerebellar ataxia, results from a polyQ expansion in the voltage gated calcium channel, Cav2.1, encoded by\n                    <jats:italic>CACNA1A<\/jats:italic>\n                    . We define a mechanism of disease in SCA6 that is related to ER stress and unrelated to impaired calcium flux function of Cav2.1. Age-related decompensation of a HSP90-dependent unfolded protein response leads to disease onset. Mutant Cav2.1 misfolding as the basis for disease in SCA6 provides insight into a novel role for channelopathies to behave as proteinopathies and helps understand resilience to proteotoxicity more widely in adult-onset neurodegenerative disease.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.27.635103","type":"posted-content","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T11:45:17Z","timestamp":1738064717000},"source":"Crossref","is-referenced-by-count":2,"title":["Resilience to Endoplasmic Reticulum Stress Mitigates Calcium-Dependent Membrane Hyperexcitability Underlying Late Disease Onset in SCA6"],"prefix":"10.64898","author":[{"given":"Haoran","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Medical Scientist Training Program, The Ohio State University College of Medicine, Columbus, OH 43210, 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