Beclin 1 mitigates motor and neuropathological deficits in genetic mouse models of Machado–Joseph disease

Abstract

Machado-Joseph disease or spinocerebellar ataxia type 3, the most common dominantly-inherited spinocerebellar ataxia, results from translation of the polyglutamine-expanded and aggregation prone ataxin 3 protein. Clinical manifestations include cerebellar ataxia and pyramidal signs and there is no therapy to delay disease progression. Beclin 1, an autophagy-related protein and essential gene for cell survival, is decreased in several neurodegenerative disorders. This study aimed at evaluating if lentiviral-mediated beclin 1 overexpression would rescue motor and neuropathological impairments when administered to pre- and post-symptomatic lentiviral-based and transgenic mouse models of Machado-Joseph disease. Beclin 1-mediated significant improvements in motor coordination, balance and gait with beclin 1-treated mice equilibrating longer periods in the Rotarod and presenting longer and narrower footprints. Furthermore, in agreement with the improvements observed in motor function beclin 1 overexpression prevented neuronal dysfunction and neurodegeneration, decreasing formation of polyglutamine-expanded aggregates, preserving Purkinje cell arborization and immunoreactivity for neuronal markers. These data show that overexpression of beclin 1 in the mouse cerebellum is able to rescue and hinder the progression of motor deficits when administered to pre- and post-symptomatic stages of the disease.

Let-7 Coordinately Suppresses Components of the Amino Acid Sensing Pathway to Repress mTORC1 and Induce Autophagy

“…As determination of autophagy pathway status in vivo is complicated, we chose to co-inject lentivirus containing a human transgene carrying a mutant ataxin-3 cDNA with 72 CAG repeats (Figure 6C), as this encodes a toxic misfolded protein product, which accumulates in aggregates in the brains of patients with spinocerebellar ataxia type 3 (Paulson et al, 1997), and can be removed by autophagy (Nascimento-Ferreira et al, 2013). LC3 immunoblot analysis of protein lysates from the brains of injected mice revealed increased levels of LC3-II relative to actin in striatal samples corresponding to the let-7 injected hemisphere (Figure 6D–E), suggesting increased autophagy pathway activation.…”

Caffeine alleviates progressive motor deficits in a transgenic mouse model of spinocerebellar ataxia

“…At 7 weeks of age, TgMJD (n 5 26) and WT (n 5 29) mice were randomly assigned to each experimental group and further provided with water (TgMJD, n 5 16; WT, n 5 16) or caffeine (TgMJD, n 5 10; WT, n 5 13) administered through the drinking water at a maximally effective and nontoxic dose (1g/L), which we have previously shown to result in a plasma concentration of 50 mM 12 and similar concentration in the brain parenchyma. 10,14 Behavioral Assessments Five TgMJD and 4 WT mice (chosen randomly) were killed at 7 weeks of age for histological and neurochemical processing; 4 mice of each experimental group (chosen randomly) were killed at 8 weeks of treatment to assess histological modifications; the remaining animals were killed after 20 weeks of treatment.…”

Autophagy in polyglutamine disease: Imposing order on disorder or contributing to the chaos?

“…Indeed, these biochemical effects of Beclin-1 overexpression translated into improved motor phenotypes in SCA3 transgenic mice, even when administered well after onset, at a stage of pathology resembling a late, severe cerebellar ataxia [64]. SCA3 models thus appear amenable to autophagy induction therapy, resulting in improvements in disease pathology when autophagy is upregulated [64].…”

“…Indeed, these biochemical effects of Beclin-1 overexpression translated into improved motor phenotypes in SCA3 transgenic mice, even when administered well after onset, at a stage of pathology resembling a late, severe cerebellar ataxia [64]. SCA3 models thus appear amenable to autophagy induction therapy, resulting in improvements in disease pathology when autophagy is upregulated [64]. In agreement with this, systemic treatment of a transgenic mouse model of SCA3 expressing ATXN3 carrying 70Q with Rapamycin analog Temsirolimus rescued motor performance and decreased aggregate number in the brain [61].…”