ULK overexpression mitigates motor deficits and neuropathology in mouse models of Machado-Joseph disease

Vasconcelos-Ferreira, Ana; Martins, Inês M.; Lobo, Diana; Pereira, Dina; Lopes, Miguel M; Faro, Rosário; Lopes, Sara; Verbeek, Dineke S.; Schmidt, Thorsten; Nóbrega, Clévio; Almeida, Luís Pereira de

doi:10.1016/j.ymthe.2021.07.012

Cited by 10 publications

(17 citation statements)

References 79 publications

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“…Dysfunction in autophagy has been linked to the pathogenesis of numerous neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and MJD, as we previously reported [14, 15]. We demonstrated that stimulation of this pathway by overexpression of beclin‐1 or ULK1 [14, 16, 17] could mitigate the disease, supporting the idea that activation of autophagy may be a suitable strategy for treatment.…”

Section: Introductionsupporting

confidence: 84%

The autophagy‐enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph disease

Vasconcelos-Ferreira

Carmo‐Silva

Codêsso

et al. 2021

Neuropathology Appl Neurobio

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Aims Machado–Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is the most common autosomal dominantly‐inherited ataxia worldwide and is characterised by the accumulation of mutant ataxin‐3 (mutATXN3) in different brain regions, leading to neurodegeneration. Currently, there are no available treatments able to block disease progression. In this study, we investigated whether carbamazepine (CBZ) would activate autophagy and mitigate MJD pathology. Methods The autophagy‐enhancing activity of CBZ and its effects on clearance of mutATXN3 were evaluated using in vitro and in vivo models of MJD. To investigate the optimal treatment regimen, a daily or intermittent CBZ administration was applied to MJD transgenic mice expressing a truncated human ATXN3 with 69 glutamine repeats. Motor behaviour tests and immunohistology was performed to access the alleviation of MJD‐associated motor deficits and neuropathology. A retrospective study was conducted to evaluate the CBZ effect in MJD patients. Results We found that CBZ promoted the activation of autophagy and the degradation of mutATXN3 in MJD models upon short or intermittent, but not daily prolonged, treatment regimens. CBZ up‐regulated autophagy through activation of AMPK, which was dependent on the myo‐inositol levels. In addition, intermittent CBZ treatment improved motor performance, as well as prevented neuropathology in MJD transgenic mice. However, in patients, no evident differences in SARA scale were found, which was not unexpected given the small number of patients included in the study. Conclusions Our data support the autophagy‐enhancing activity of CBZ in the brain and suggest this pharmacological approach as a promising therapy for MJD and other polyglutamine disorders.

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Section: Introductionsupporting

confidence: 84%

The autophagy‐enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph disease

Vasconcelos-Ferreira

Carmo‐Silva

Codêsso

et al. 2021

Neuropathology Appl Neurobio

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“…ULK1 is a protein important in the formation of autophagosomes [ 6 , 32 ]. Vasconcelos-Ferreira et al (2022) have recently reported decreased ULK1 transcript levels in samples from SCA3 patients and murine models of SCA3 [ 33 ]. We hypothesise that the two ULK1 isoforms identified within our study are the ULK1 protein (110 kDa) and ULK1 with a post-translational modification (PTM), such as phosphorylation (120 kDa).…”

Section: Discussionmentioning

confidence: 99%

“…They also found that beclin-1 levels were reduced in SCA3 patient fibroblasts [ 19 ]. Since then, several studies have shown evidence of autophagy impairment within SCA3 patient brain samples [ 18 , 20 , 21 , 33 ]. Future studies to examine immunohistochemical co-staining of the brains of aging SCA3 zebrafish for autophagy machinery and ataxin-3 would be valuable.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Function and Benefits of Autophagy Induction in Models of Spinocerebellar Ataxia Type 3

Watchon

Luu

Plenderleith

et al. 2023

Cells

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Background: Spinocerebellar ataxia 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. The presence of this genetic expansion results in an ataxin-3 protein containing a polyglutamine repeat region, which renders the ataxin-3 protein aggregation prone. Formation of ataxin-3 protein aggregates is linked with neuronal loss and, therefore, the development of motor deficits. Methods: Here, we investigated whether the autophagy protein quality control pathway, which is important in the process of protein aggregate removal, is impaired in a cell culture and zebrafish model of SCA3. Results: We found that SH-SY5Y cells expressing human ataxin-3 containing polyglutamine expansion exhibited aberrant levels of autophagy substrates, including increased p62 and decreased LC3II (following bafilomycin treatment), compared to the controls. Similarly, transgenic SCA3 zebrafish showed signs of autophagy impairment at early disease stages (larval), as well as p62 accumulation at advanced age stages (18 months old). We then examined whether treating with compounds known to induce autophagy activity, would aid removal of human ataxin-3 84Q and improve the swimming of the SCA3 zebrafish larvae. We found that treatment with loperamide, trehalose, rapamycin, and MG132 each improved the swimming of the SCA3 zebrafish compared to the vehicle-treated controls. Conclusion: We propose that signs of autophagy impairment occur in the SH-SY5Y model of SCA3 and SCA3 zebrafish at larval and advanced age stages. Treatment of the larval SCA3 zebrafish with various compounds with autophagy induction capacity was able to produce the improved swimming of the zebrafish, suggesting the potential benefit of autophagy-inducing compounds for the treatment of SCA3.

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“…Several attempts to correct autophagy in MJD have been made either by inducing the overexpression of ULK or beclin-1, or by administrating autophagy enhancing drugs, such as carbamazepine or trehalose, achieving good results. [109][110][111][112] A clear relationship between lysosomal dysfunction and autophagy impairments was established for LSDs. In fact, besides storage, there are many secondary effects caused by the dysfunction of the lysosomalautophagy machinery, such as exocytosis, cholesterol homeostasis and unbalance of crucial cellular pathways that are associated with the control of cell death, differentiation and proliferation or immune response (reviewed in 102 ).…”

Section: Better Proteostasis and Autophagy Cycling Turnovermentioning

confidence: 99%

“…In MJD, autophagy is decreased by the accumulation of mutant ataxin‐3 that tends to form both soluble toxic fragments and insoluble aggregates. Several attempts to correct autophagy in MJD have been made either by inducing the overexpression of ULK or beclin‐1, or by administrating autophagy enhancing drugs, such as carbamazepine or trehalose, achieving good results 109‐112 . A clear relationship between lysosomal dysfunction and autophagy impairments was established for LSDs.…”

Section: Possible Common Targets Of Msc In Lsds and Polyqsmentioning

confidence: 99%

Mesenchymal stem cells for lysosomal storage and polyglutamine disorders: Possible shared mechanisms

Miranda

2021

Eur J Clin Investigation

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Background Mesenchymal stem cells' (MSC) therapeutic potential has been investigated for the treatment of several neurodegenerative diseases. The fact these cells can mediate a beneficial effect in different neurodegenerative contexts strengthens their competence to target diverse mechanisms. On the other hand, distinct disorders may share similar mechanisms despite having singular neuropathological characteristics. Methods We have previously shown that MSC can be beneficial for two disorders, one belonging to the groups of Lysosomal Storage Disorders (LSDs) – the Krabbe Disease or Globoid Cell Leukodystrophy, and the other to the family of Polyglutamine diseases (PolyQs) – the Machado‐Joseph Disease or Spinocerebellar ataxia type 3. We gave also input into disease characterization since neuropathology and MSC's effects are intrinsically associated. This review aims at describing MSC's multimode of action in these disorders while emphasizing to possible mechanistic alterations they must share due to the accumulation of cellular toxic products. Results Lysosomal storage disorders and PolyQs have different aetiology and associated symptoms, but both result from the accumulation of undegradable products inside neuronal cells due to inefficient clearance by the endosomal/lysosomal pathway. Moreover, numerous cellular mechanisms that become compromised latter are also shared by these two disease groups. Conclusions Here, we emphasize MSC's effect in improving proteostasis and autophagy cycling turnover, neuronal survival, synaptic activity and axonal transport. LSDs and PolyQs, though rare in their predominance, collectively affect many people and require our utmost dedication and efforts to get successful therapies due to their tremendous impact on patient s' lives and society.

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ULK overexpression mitigates motor deficits and neuropathology in mouse models of Machado-Joseph disease

Cited by 10 publications

References 79 publications

The autophagy‐enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph disease

The autophagy‐enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph disease

Autophagy Function and Benefits of Autophagy Induction in Models of Spinocerebellar Ataxia Type 3

Mesenchymal stem cells for lysosomal storage and polyglutamine disorders: Possible shared mechanisms

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