Protein Clearance Mechanisms of Alpha-Synuclein and Amyloid-Beta in Lewy Body Disorders

Deleidi, Michela; Maetzler, Walter

doi:10.1155/2012/391438

Cited by 31 publications

(24 citation statements)

References 133 publications

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“…Besides the proteasomal degradation, autophagic clearance of α-synuclein aggregates has also been observed in higher eukaryotes (Deleidi and Maetzler, 2012;Pan et al, 2008;Webb et al, 2003). In line with these findings, autophagic induction by the TOR inhibitor rapamycin resulted in a significant reduction in α-synuclein inclusions in the PD yeast model (Zabrocki et al, 2005).…”

Section: Yeast Models To Study Parkinson's Disease Associated Genessupporting

confidence: 67%

Yeast buddies helping to unravel the complexity of neurodegenerative disorders

Fruhmann

Seynnaeve

Zheng

et al. 2017

Mechanisms of Ageing and Development

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Section: Yeast Models To Study Parkinson's Disease Associated Genessupporting

confidence: 67%

Yeast buddies helping to unravel the complexity of neurodegenerative disorders

Fruhmann

Seynnaeve

Zheng

et al. 2017

Mechanisms of Ageing and Development

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“…Compelling evidence suggests that neurodegeneration in PD involves dysregulation of autophagy, e.g., autophagosomes and protein aggregates have been observed in PD post-mortem brains (Malagelada et al, 2010). Different models show that impaired autophagy in dopaminergic neurons is coupled to aggregation of α-synuclein (Pan et al, 2008), akin to the Lewy aggregates found in dopamine neuron terminals in PD (Deleidi and Maetzler, 2012). …”

Section: Discussionmentioning

confidence: 99%

Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease

Nordström

Beauvais

Ghosh

et al. 2015

Neurobiology of Disease

111

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Current research on Parkinson’s disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1+/– mice with focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1+/– mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra (SN) could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of En1+/– mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of En1+/ – mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1+/– nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using En1+/– mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.

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“…1). Mechanisms of clearance include proteolysis, autophagy, and proteasomal degradation [37,38]. In this context, it has been suggested that Aβ, tau, and α-syn toxic aggregates might be major therapeutic targets for these neurodegenerative disorders (Fig.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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Protein Clearance Mechanisms of Alpha-Synuclein and Amyloid-Beta in Lewy Body Disorders

Cited by 31 publications

References 133 publications

Yeast buddies helping to unravel the complexity of neurodegenerative disorders

Yeast buddies helping to unravel the complexity of neurodegenerative disorders

Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

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