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

2021 ◽  
Author(s):  
Ana Vasconcelos‐Ferreira ◽  
Sara Carmo‐Silva ◽  
José Miguel Codêsso ◽  
Patrick Silva ◽  
Alberto Rolim Muro Martinez ◽  
...  
Keyword(s):  
Mouse Models ◽  
Motor Impairment ◽  
Machado Joseph Disease

scholarly journals Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Janete Cunha-Santos ◽  
Joana Duarte-Neves ◽  
Vitor Carmona ◽  
Leonard Guarente ◽  
Luís Pereira de Almeida ◽  
...  
Keyword(s):  
Caloric Restriction ◽  
Mouse Models ◽  
Motor Deficits ◽  
Machado Joseph Disease

scholarly journals Synaptic RTP801 contributes to motor-learning dysfunction in Huntington’s disease

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Núria Martín-Flores ◽  
Leticia Pérez-Sisqués ◽  
Jordi Creus-Muncunill ◽  
Mercè Masana ◽  
Sílvia Ginés ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Motor Learning ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Motor Impairment ◽  
Motor Dysfunction ◽  
Protein Levels ◽  
Cellular Models ◽  
Learning Impairment

Abstract RTP801/REDD1 is a stress-responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington’s disease (HD) patients’ putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. To explore this hypothesis, ectopic mhtt was over expressed in cultured rat primary neurons. Moreover, the protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Finally, striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor-learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.

Pathophysiological interplay between O-GlcNAc transferase and the Machado–Joseph disease protein ataxin-3

2021 ◽  
Vol 118 (47) ◽  
pp. e2025810118
Author(s):  
Priscila Pereira Sena ◽  
Jonasz J. Weber ◽  
Maxinne Watchon ◽  
Katherine J. Robinson ◽  
Zinah Wassouf ◽  
...  
Keyword(s):  
Motor Impairment ◽  
Direct Interaction ◽  
Dependent Manner ◽  
Zebrafish Model ◽  
Protein Levels ◽  
Polyglutamine Disorders ◽  
Neuronal Proteins ◽  
Disease Protein ◽  
Machado Joseph Disease ◽  
Glcnac Transferase

Aberrant O-GlcNAcylation, a protein posttranslational modification defined by the O-linked attachment of the monosaccharide N-acetylglucosamine (O-GlcNAc), has been implicated in neurodegenerative diseases. However, although many neuronal proteins are substrates for O-GlcNAcylation, this process has not been extensively investigated in polyglutamine disorders. We aimed to evaluate the enzyme O-GlcNAc transferase (OGT), which attaches O-GlcNAc to target proteins, in Machado–Joseph disease (MJD). MJD is a neurodegenerative condition characterized by ataxia and caused by the expansion of a polyglutamine stretch within the deubiquitinase ataxin-3, which then present increased propensity to aggregate. By analyzing MJD cell and animal models, we provide evidence that OGT is dysregulated in MJD, therefore compromising the O-GlcNAc cycle. Moreover, we demonstrate that wild-type ataxin-3 modulates OGT protein levels in a proteasome-dependent manner, and we present OGT as a substrate for ataxin-3. Targeting OGT levels and activity reduced ataxin-3 aggregates, improved protein clearance and cell viability, and alleviated motor impairment reminiscent of ataxia of MJD patients in zebrafish model of the disease. Taken together, our results point to a direct interaction between OGT and ataxin-3 in health and disease and propose the O-GlcNAc cycle as a promising target for the development of therapeutics in the yet incurable MJD.

scholarly journals Neuropeptide Y mitigates neuropathology and motor deficits in mouse models of Machado–Joseph disease

2015 ◽  
Vol 24 (19) ◽  
pp. 5451-5463 ◽  
Author(s):  
Joana Duarte-Neves ◽  
Nélio Gonçalves ◽  
Janete Cunha-Santos ◽  
Ana Teresa Simões ◽  
Wilfred F.A. den Dunnen ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Mouse Models ◽  
Motor Deficits ◽  
Machado Joseph Disease

scholarly journals Calpain inhibition reduces ataxin-3 cleavage alleviating neuropathology and motor impairments in mouse models of Machado–Joseph disease

2014 ◽  
Vol 23 (18) ◽  
pp. 4932-4944 ◽  
Author(s):  
Ana Teresa Simões ◽  
Nélio Gonçalves ◽  
Rui Jorge Nobre ◽  
Carlos Bandeira Duarte ◽  
Luís Pereira de Almeida
Keyword(s):  
Mouse Models ◽  
Motor Impairments ◽  
Machado Joseph Disease ◽  
Calpain Inhibition

scholarly journals Degeneration of ipRGCs in Mouse Models of Huntington's Disease Disrupts Non-Image-Forming Behaviors Before Motor Impairment

2018 ◽  
Vol 39 (8) ◽  
pp. 1505-1524 ◽  
Author(s):  
Meng-Syuan Lin ◽  
Po-Yu Liao ◽  
Hui-Mei Chen ◽  
Ching-Pang Chang ◽  
Shih-Kuo Chen ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Motor Impairment
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