Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In familial and sporadic forms of Parkinson's disease (PD), alpha-synuclein pathology is present in the brain stem nuclei and olfactory bulb (OB) long before Lewy bodies are detected in the substantia nigra. The OB is an active region of adult neurogenesis, where newly generated neurons physiologically integrate. While accumulation of wild-type alpha-synuclein is one of the pathogenic hallmarks of non-genetic forms of PD, the A30P alpha-synuclein mutation results in an earlier disease onset and a severe clinical phenotype. Here, we study the regulation of adult neurogenesis in the subventricular zone (SVZ)/OB system in a tetracycline-suppressive (tet-off) transgenic model of synucleinopathies, expressing human mutant A30P alpha-synuclein under the control of the calcium/calmodulin-dependent protein kinase II alpha (CaMK) promoter. In A30P transgenic mice alpha-synuclein was abundant at the site of integration in the glomerular cell layer of the OB. Without changes in proliferation in the SVZ, significantly fewer newly generated neurons were observed in the OB granule cell and glomerular layers of A30P transgenic mice than in controls, most probably due to increased cell death. By tetracycline-dependent abrogation of A30P alpha-synuclein expression, OB neurogenesis and programmed cell death was restored to control levels. Our results indicate that, using A30P conditional (tet-off) mice, A30P alpha-synuclein has a negative impact on olfactory neurogenesis and suppression of A30P alpha-synuclein enhances survival of newly generated neurons. This finding suggests that interfering with alpha-synuclein pathology can rescue newly generated neurons, possibly leading to new targets for therapeutic interventions in synucleinopathies.
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PMID:Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein. 1929 Dec 19

Accumulation and aggregation of alpha-synuclein in cortical and hippocampal areas is a pathological sign for dementia with Lewy bodies (DLB) and Parkinson's disease with dementia. However the mechanisms of alpha-synuclein triggered cellular dysfunction leading to the development of memory impairment is not clear. We have created a mouse model of DLB, where aggregation-prone human truncated (120 amino acid) alpha-synuclein is expressed in forebrain areas under the calcium/calmodulin-dependent protein kinase II alpha (CamKII-alpha) promoter. We have observed the presence of the transgenic protein in target forebrain areas, with small granular cytoplasmic accumulation of aggregated alpha-synuclein. This was associated with a progressive deficit in cortical-hippocampal memory tests including the Barnes maze and novel object recognition. This data suggests that low levels of aggregation prone alpha-synuclein are sufficient to induce memory deficits in mice and that forebrain regions associated with cognitive function may have an increased sensitivity to the truncated toxic form of alpha-synuclein.
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PMID:Behavioural deficits in transgenic mice expressing human truncated (1-120 amino acid) alpha-synuclein. 2545 Apr 66