Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson’s disease

Meredith, Gloria E.; Totterdell, Susan; Petroske, Elizabeth; Cruz, K Santa; Callison, R.C; Lau, Yuen-Sum

doi:10.1016/s0006-8993(02)03514-x

Cited by 192 publications

(133 citation statements)

References 45 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…However, a chronic model with implanted osmotic pumps delivering constant small amounts of the toxin would have been a more optimal model to mimic the disease (385). Despite prolonged administration, however, MPTP does not generate Lewy bodies (76), although it has been described in a few cases (386,387). In line with this, intracytoplasmic inclusions were not observed in our model.…”

Section: Mptp Model Of Pdsupporting

confidence: 87%

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

et al. 2011

View full text Add to dashboard Cite

Section: Mptp Model Of Pdsupporting

confidence: 87%

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

et al. 2011

View full text Add to dashboard Cite

“…Furthermore, these models should prove useful for the investigation of neurodegenerative mechanisms characterized by delayed onset and slow progression over years or decades. Indeed, oxidative stress and mitochondrial dysfunction, as well as activation of autophagy in several of the major human neurodegenerative disorders, including Alzheimer's disease (Nixon et al, 2000;Hirai et al, 2001;Perry et al, 2002), Parkinson's disease (Anglade et al, 1997;Meredith et al, 2002), and Huntington's disease (Kegel et al, 2000), have been reported repeatedly, although their role in these pathologies is still discussed. The novel spatiotemporally controlled conditional gene-targeting approach that we have used is particularly adapted to study the mechanisms of lateonset and slowly progressive neurodegeneration and is amenable to large experimental flexibility through modulation at will of the timing of induction.…”

Section: Discussionmentioning

confidence: 99%

Friedreich Ataxia Mouse Models with Progressive Cerebellar and Sensory Ataxia Reveal Autophagic Neurodegeneration in Dorsal Root Ganglia

Simon¹,

Seznec²,

Gansmüller³

et al. 2004

J. Neurosci.

177

139

View full text Add to dashboard Cite

Friedreich ataxia (FRDA), the most common recessive ataxia, is characterized by degeneration of the large sensory neurons of the spinal cord and cardiomyopathy. It is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biosynthesis. Through a spatiotemporally controlled conditional gene-targeting approach, we have generated two mouse models for FRDA that specifically develop progressive mixed cerebellar and sensory ataxia, the most prominent neurological features of FRDA. Histological studies showed both spinal cord and dorsal root ganglia (DRG) anomalies with absence of motor neuropathy, a hallmark of the human disease. In addition, one line revealed a cerebellar granule cell loss, whereas both lines had Purkinje cell arborization defects. These lines represent the first FRDA models with a slowly progressive neurological degeneration. We identified an autophagic process as the causative pathological mechanism in the DRG, leading to removal of mitochondrial debris and apparition of lipofuscin deposits. These mice therefore represent excellent models for FRDA to unravel the pathological cascade and to test compounds that interfere with the degenerative process.

show abstract

“…The formation of inclusion bodies has been demonstrated for several chronic MPTP models, but not for acute or subchronic models [7][8][9][10][11]. Presumably, the slow administration of MPTP/ p can induce prolonged damage to mitochondria and precipitate alpha-synuclein toxicity, resulting in cytoplasmic accumulation of alpha-synuclein and ubiquitin proteins.…”

Section: Dopamine Loss Motor Dysfunction Inflammation and Inclusionmentioning

confidence: 99%

Modeling PD pathogenesis in mice: Advantages of a chronic MPTP protocol

Meredith

Totterdell

Potashkin

et al. 2008

Parkinsonism & Related Disorders

174

138

View full text Add to dashboard Cite

Formidable challenges for Parkinson's disease (PD) research are to understand the processes underlying nigrostriatal degeneration and how to protect the dopamine neurons. Fundamental research relies on good animal models that demonstrate the pathological hallmarks and motor deficits of PD. Using a chronic regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p) in mice, dopamine cell loss exceeds 60%, extracellular glutamate is elevated, cytoplasmic inclusions are formed and inflammation is chronic. Nevertheless, isradipine, an L-type calciumchannel blocker, attenuates the degeneration. These data support the validity of the MPTP/p model for unravelling the degenerative processes in PD and testing therapies that slow their progress.

show abstract

Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson’s disease

Cited by 192 publications

References 45 publications

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

Friedreich Ataxia Mouse Models with Progressive Cerebellar and Sensory Ataxia Reveal Autophagic Neurodegeneration in Dorsal Root Ganglia

Modeling PD pathogenesis in mice: Advantages of a chronic MPTP protocol

Contact Info

Product

Resources

About