The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Abstract

Polyglutamine diseases are a class of neurodegenerative diseases that share an expansion of a glutamineencoding CAG tract in the respective disease genes as a central hallmark. In all of these diseases there is progressive degeneration in a select subset of neurons, and the mechanisms behind this degeneration remain unclear. Emerging evidence from animal models of disease has identified abnormalities in synaptic signaling and intrinsic excitability in affected neurons, which coincide with the onset of symptoms and precede apparent neuropathology. The appearance of these early changes suggests that altered neuronal activity might be an important component of network dysfunction and that these alterations in network physiology could contribute to symptoms of disease. Here we review abnormalities in neuronal function that have been identified in both animal models and patients, and highlight ways in which these changes in neuronal activity may contribute to disease symptoms. We then review the literature supporting an emerging role for abnormalities in neuronal activity as a driver of neurodegeneration. Finally, we identify common themes that emerge from studies of neuronal dysfunction in polyglutamine disease.

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“…For example, in stroke, the infarct core is surrounded by the hypoxic area (ischemic penumbra) and the ischemic brain area contains functionally silent neurons that can be rescued before they undergo cell death [43]. In addition, in the early stages of degenerative diseases, functional impairment (e.g., synaptic dysfunction or signal flow in cerebellar circuits) that precedes degenerative cell loss can advance to clinically evident CAs [44,45]. In general, the following therapeutic strategy can be applied irrespective of etiology: (1) curative treatments should be designed in the initial stages to minimize damage to the cerebellum while cerebellar impairment is still within the frame of functional disorder with adequate cerebellar reserve; (2) neuromodulation therapy should be followed to [37], certain medications (aminopyridine) [46], or noninvasive cerebellar stimulation [47].…”

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“…The dysregulation of calcium signaling is found in many different neurodegenerative traits, and its role in the pathophysiology of these disorders has been the subject of many extensive reviews (Chopra and Shakkottai, 2014; Egorova et al, 2015; Meera et al, 2016). In SCA2 research, there is compelling evidence of abnormal calcium signaling, to which the PCs seem to be particularly susceptible, triggering the very first physical symptoms of the disease (Kasumu and Bezprozvanny, 2012).…”

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“…1,2 Recent studies indicate that abnormal neuronal activity precedes the cell loss while the site and mechanism of degeneration is specific to the disease itself. 3 A characteristic cross-b structure is observed in all polyglutamine fibrils. 4,5 A major distinction between polyQ peptides and other amyloids is the nature of this cross-b structure.…”