Abstract
Spinocerebellar ataxia 1 (SCA1) is a devastating neurodegenerative disease associated with cerebellar degeneration and motor deficits. However, many patients also exhibit neuropsychiatric impairments such as depression and apathy; nevertheless, the existence of a causal link between the psychiatric symptoms and SCA1 neuropathology remains controversial. This study aimed to explore behavioral deficits in a knock-in mouse SCA1 (SCA1154Q/2Q) model and to identify the underlying neuropathology. We found that the SCA1 mice exhibit previously undescribed behavioral impairments such as increased anxiety- and depressive-like behavior and reduced prepulse inhibition and cognitive flexibility. Surprisingly, non-motor deficits characterize the early SCA1 stage in mice better than does ataxia. Moreover, the SCA1 mice exhibit significant hippocampal atrophy with decreased plasticity-related markers and markedly impaired neurogenesis. Interestingly, the hippocampal atrophy commences earlier than the cerebellar degeneration and directly reflects the individual severity of some of the behavioral deficits. Finally, mitochondrial respirometry suggests profound mitochondrial dysfunction in the hippocampus, but not in the cerebellum of the young SCA1 mice. These findings imply the essential role of hippocampal impairments, associated with profound mitochondrial dysfunction, in SCA1 behavioral deficits. Moreover, they underline the view of SCA1 as a complex neurodegenerative disease and suggest new avenues in the search for novel SCA1 therapies.
Highlights
Spinocerebellar ataxia 1 (SCA1) is a devastating neurodegenerative disease associated with cerebellar degeneration and motor deficits
Recent findings have highlighted the role of mitochondrial dysfunctions in the cerebellar pathophysiology of SCA123–25 and that ataxin-1 encoding gene (ATXN1) plays a role in mitochondrial bioenergetics[26], no examination of non-cerebellar mitochondrial functions in SCA1 has been conducted to date
We demonstrate that these deficits precede substantial ataxia and further suggest hippocampal impairments, associated with profound mitochondrial dysfunction, as the underlying neuropathology thereof
Summary
Spinocerebellar ataxia 1 (SCA1) is a devastating neurodegenerative disease associated with cerebellar degeneration and motor deficits. In contrast to progressive ataxia, the psychiatric impairments tend to remain relatively stable over time[8] They are often overlooked, they profoundly impact the quality of life and health outcomes of patients with SCA1 and related diseases[9]. In addition to cerebellar pathology and motor deficits, the SCA1154Q/2Q mice exhibit learning impairments and an alteration to hippocampal plasticity-related functions such as synaptic dynamic disruption, synaptic loss and impaired neural progenitor cell proliferation[11,12,13,14]. It is not clear whether the hippocampal dysfunctions are directly linked to the SCA1 non-motor symptoms. Recent findings have highlighted the role of mitochondrial dysfunctions in the cerebellar pathophysiology of SCA123–25 and that ATXN1 plays a role in mitochondrial bioenergetics[26], no examination of non-cerebellar mitochondrial functions in SCA1 has been conducted to date
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