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See detailOlfactory neuron-specific expression of A30P alpha-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages.
Nuber, Silke; Petrasch-Parwez, Elisabeth; Arias-Carrion, Oscar et al

in Neurobiology of Disease (2011), 44(2), 192-204

Mutations in the N-terminus of the gene encoding alpha-synuclein (alpha-syn) are linked to autosomal dominantly inherited Parkinson's disease (PD). The vast majority of PD patients develop ... [more ▼]

Mutations in the N-terminus of the gene encoding alpha-synuclein (alpha-syn) are linked to autosomal dominantly inherited Parkinson's disease (PD). The vast majority of PD patients develop neuropsychiatric symptoms preceding motor impairments. During this premotor stage, synucleinopathy is first detectable in the olfactory bulb (OB) and brain stem nuclei; however its impact on interconnected brain regions and related symptoms is still less far understood. Using a novel conditional transgenic mouse model, displaying region-specific expression of human mutant alpha-syn, we evaluated effect and reversibility of olfactory synucleinopathy. Our data showed that induction of mutant A30P alpha-syn expression increased transgenic deposition into somatodendritic compartment of dopaminergic neurons, without generating fibrillar inclusions. We found reversibly reduced levels of dopamine and metabolites in the OB, suggesting an impact of A30P alpha-syn on olfactory neurotransmitter content. We further showed that mutant A30P expression led to neurodegenerative changes on an ultrastructural level and a behaviorally hyperactive response correlated with novelty, odor processing and stress associated with an increased dopaminergic tone in midbrain regions. Our present data indicate that mutant (A30P) alpha-syn is directly implicated in reduction of dopamine signaling in OB interneurons, which mediates further alterations in brain regions without transgenic expression leading functionally to a hyperactive response. These modulations of neurotransmission may underlie in part some of the early neuropsychiatric symptoms in PD preceding dysfunction of the nigrostriatal dopaminergic system. [less ▲]

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See detailFirst appraisal of brain pathology owing to A30P mutant alpha-synuclein.
Seidel, Kay; Schols, Ludger; Nuber, Silke et al

in Annals of neurology (2010), 67(5), 684-9

Familial Parkinson disease (PD) due to the A30P mutation in the SNCA gene encoding alpha-synuclein is clinically associated with PD symptoms. In this first pathoanatomical study of the brain of an A30P ... [more ▼]

Familial Parkinson disease (PD) due to the A30P mutation in the SNCA gene encoding alpha-synuclein is clinically associated with PD symptoms. In this first pathoanatomical study of the brain of an A30P mutation carrier, we observed neuronal loss in the substantia nigra, locus coeruleus, and dorsal motor vagal nucleus, as well as widespread occurrence of alpha-synuclein immunopositive Lewy bodies, Lewy neurites, and glial aggregates. Alpha-synuclein aggregates ultrastructurally resembled Lewy bodies, and biochemical analyses disclosed a significant load of insoluble alpha-synuclein, indicating neuropathological similarities between A30P disease patients and idiopathic PD, with a more severe neuropathology in A30P carriers. [less ▲]

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