The coaggregation of the amyloid-β peptide (Aβ) and α-synuclein is commonly observed in a range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. The complex interplay between Aβ and α-synuclein has led to seemingly contradictory results on whether α-synuclein promotes or inhibits Aβ aggregation. Here, we show how these conflicts can be rationalized and resolved by...

Many neurodegenerative diseases are characterized by the accumulation of insoluble protein aggregates, including neurofibrillary tangles comprised of tau in Alzheimer's disease and Lewy bodies composed of α-synuclein in Parkinson's disease. Moreover, different pathological proteins frequently codeposit in disease brains. To test whether aggregated α-synuclein can directly cross-seed tau fibrill...

Abnormal α-synuclein aggregates are hallmarks of a number of neurodegenerative diseases. Alpha synuclein and β-synucleins are susceptible to post-translational modification as isoaspartate protein damage, which is regulated in vivo by the action of the repair enzyme protein L-isoaspartyl O-methyltransferase (PIMT). We aged in vitro native α-synuclein, the α-synuclein familial mutants A30P and A...

It is well established that the abundant neuronal protein ␣-synuclein has a causal role in Parkinson's disease , yet the normal functions of this protein remain unclear. In this issue of Cell, Chandra et al. (2005) reveal that ␣-synuclein acts as a molecular chaperone, assisting in the folding and refolding of synaptic proteins called SNAREs. These proteins are crucial for release of neurotrans...

In Parkinson's disease (PD) there is widespread accumulation in the brain of abnormal α-synuclein aggregates forming intraneuronal Lewy bodies (LB). It is now well established that LB-type α-synuclein aggregates also occur in the peripheral autonomic nervous system in PD, from where it has been speculated they may progressively spread to the central nervous system through synaptically-connected...

Mutations in the genes encoding LRRK2 and α-synuclein cause autosomal dominant forms of familial Parkinson's disease (PD). Fibrillar forms of α-synuclein are a major component of Lewy bodies, the intracytoplasmic proteinaceous inclusions that are a pathological hallmark of idiopathic and certain familial forms of PD. LRRK2 mutations cause late-onset familial PD with a clinical, neurochemical an...

Seung-Jae Lee, Konkuk University Review of exocytosis, extracellular forms and extracellular interactions critical for -synuclein pathology Dr. Lee described synuclein exocytosis as not a robust eventonly small amounts are released, but they occur without membrane damage and are temperature dependent, and therefore result from active processes. The presence of -synuclein in CSF and plasma sug...

α-Synuclein is a presynaptic protein that regulates synaptic vesicle (SV) trafficking. In Parkinson's disease (PD) and several other neurodegenerative disorders, aberrant oligomerization and aggregation of α-synuclein lead to synaptic dysfunction and neurotoxicity. Despite evidence that α-synuclein oligomers are generated within neurons under physiological conditions, and that altering the bala...

Mutation A30P in the a-synuclein gene is a cause of familial Parkinson disease. Transgenic mice expressing wild mouse and mutant human A30P a-synuclein, Tg5093 mice (Tg), show a progressive motor disorder characterized by tremor, rigidity, and dystonia, accompanied by accumulation of a-synuclein in the soma and neurites and by a conspicuous gliosis beginning in the hippocampal formation at the ...

We have previously reported that pyrroloquinoline quinone (PQQ) prevents the amyloid formation of α-synuclein, amyloid β(1-42) (Aβ(1-42)), and mouse prion protein. Moreover, PQQ-modified α-synuclein and a proteolytic fragment of the PQQ-modified α-synuclein are able to inhibit the amyloid formation of α-synuclein. Here, we identified the peptide sequences that play an important role as PQQ-mod...