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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 detailIdentification and functional dissection of localization signals within ataxin-3.
Antony, Paul UL; Mäntele, Simone; Mollenkopf, Phillip et al

in Neurobiology of Disease (2009), 36(2), 280-92

Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD) belongs to a group of autosomal dominant neurodegenerative diseases, which are caused by the expansion of a polyglutamine repeat in the ... [more ▼]

Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD) belongs to a group of autosomal dominant neurodegenerative diseases, which are caused by the expansion of a polyglutamine repeat in the affected protein, in this case ataxin-3. Ataxin-3 is mainly localized in the cytoplasm; however, one hallmark of SCA3 is the formation of ataxin-3-containing protein aggregates in the nucleus of neurons. Currently, it is not known how mutant ataxin-3 translocates into the nucleus. We performed localization assays of recently proposed and novel potential signals, functionally confirmed the activity of a nuclear localization signal, identified two novel nuclear export signals (NES 77 and NES 141), and determined crucial amino acids. In addition, we demonstrate the relevance of the identified signals for the intracellular localization of the N- and C-terminus of ataxin-3. Our findings stress the importance of investigating the mechanisms, which influence the intracellular distribution of ataxin-3 during the pathogenesis of SCA3. [less ▲]

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