It has an essential role in normal cytoplasmic turnover and eliminating damaged, dysfunctional, and unused cellular components. Autophagy is a lysosomal degradation pathway that is present at a basal level in all eukaryotic cells and ensures steady-state homeostasis.
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Several studies have demonstrated that the presence of mHTT interrupts macroautophagy (hereafter referred to as autophagy), contributing to the impaired clearance of aggregated proteins. There is a clear negative correlation between the number of CAG repeats and the disease onset, whereas the age-dependent neuronal loss and the severity of symptoms positively correlate with the accumulation of mHTT into protein aggregates. Consequently, mutant HTT (mHTT) is more prone to form oligomers and eventually aggregates into the inclusions that characterize the disease histologically. At a molecular level, the disease is caused by an expansion of CAG trinucleotide repeats in the first exon of the HTT (huntingtin) gene, which results in an elongated polyQ stretch in the mutated protein. HD is a fatal disorder characterized by involuntary movements coupled with cognitive impairment and emotional lability, with no efficient treatment currently available. Huntington disease (HD) is a neurodegenerative disorder that is inherited in an autosomal dominant fashion and exhibits, as part of its core pathology, a predominant loss of cortical and striatal medium spiny neurons.
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Abbreviations: AAV: adeno-associated viral vectors ACTB: actin beta BECN1: beclin 1, autophagy related DAPI: 4ʹ,6-diamidino-2-phenylindole GO: gene ontology HD: Huntington disease HTT: huntingtin ICQ: Li’s intensity correlation quotient IHC: immunohistochemistry LAMP1: lysosomal-associated membrane protein 1 MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta mHTT: mutant huntingtin PCA: principal component analysis PPP1R1B/DARPP-32: protein phosphatase 1 regulatory inhibitor subunit 1B SQSTM1: sequestosome 1 TFEB: transcription factor EB WB: western blot WT: wild-type. Together, these results demonstrate that the targets used to activate autophagy, as well as the timing of autophagy activation, are crucial for achieving efficient therapeutic effects. When Becn1 was administered at a later stage, when prominent mutant HTT accumulation and autophagy impairments have occurred, Becn1 overexpression did not rescue the mutant HTT-associated phenotypes. On the other hand, Becn1 overexpression, an autophagic regulator that plays a key role in autophagosome formation, partially cleared mutant HTT aggregates and restored neuronal pathology, but only when administered early in the disease progression. We found that overexpression of human TFEB, a master regulator of autophagy, did not decrease mutant HTT aggregation. In this study, we used a mouse model of HTT (huntingtin) protein aggregation to investigate how different methods and timing of autophagy activation influence the efficacy of autophagy-activating treatment in vivo. How neuronal autophagy impairments need to be considered in Huntington disease progression to achieve a therapeutic effect is currently not known. Activation of macroautophagy/autophagy, a key mechanism involved in the degradation and removal of aggregated proteins, can successfully reverse Huntington disease phenotypes in various model systems.