[The role of parkin in Parkinson's disease]. / A parkin szerepe a Parkinson-kórban.

Parkin (Parkinson juvenile disease protein 2) is a ~52 kDa (426 amino acid) enzyme protein, encoded by PARK2 gene and located on the 6q chromosome. It plays an important role in the ubiquitin-proteasome system and acts as a regulator of protein breakdown. Parkin is located in the cytoplasma until a sustained depolarization occurs as a result of which it is translocated to the mitochondrial surface and induces the degradation of various membrane proteins which are candidates for mitophagia. Parkin is essential for cellular mitochondrial integrity. Parkin mutation leads to the accumulation of missfolded, aggregated proteins and degenerated mitochondria. The role of these changes in the pathomechanism of neurodegenerative diseases is well-known. It was a general belief for a long time that Parkinson's disease is without genetic component a sporadic disease. In 1997 a point mutation was, however, discovered in the α-synuclein gene, which caused dominantly inherited parkinsonism. At least 10 other genes were thereafter detected the mutation or deletion of which cause monogenic parkinsonism. Parkin mutation is responsible for about 50% of familial cases and for 10 to 20% of youth cases. According to the present views the improper regulation of protein aggregation and a dysfunction of the ubiquitin-proteasome system may be the common pathway of sporadic and hereditary Parkinson's disease. In the future it might have therapeutic value that parkin has versatile neuroprotective activity (against α-synuclein toxicity, proteasomal dysfunction, oxidative stress, kainite-induced and dopamine-mediated toxicity) as a result of which any reduction of parkin level or activity may cause damage in neuronal integrity.

[The role of alpha-synuclein in Parkinson's disease]. / Az α-szinuklein szerepe Parkinson-kórban.

α-synuclein, a small protein (140 amino acids) encoded by the SNCA gene is the best known isoform of the synuclein protein family. Though its physiological role is still not fully clarified, there is growing experimental evidence for a causal role of α-synuclein in the so-called conformational-neurodegenerative diseases. Conformational changes in the structure of the native soluble protein form insoluble neurotoxic aggregates and finally contribute to the formation of inclusion Lewy-bodies and Lewy-neurites. Neurodegeneration first hits the olfactory system, the peripheral autonomic nervous system, the enteric nervous system and the dorsal vagal motoneurons. The middle stage of the disease hits the dopaminergic neurons of the substantia nigra; and the neocortex is affected only in the late stage of the disease. This precise order of neurodegeneration is not always valid, but increases the likelihood that Lewy-bodies and neurodegenaration spread to intact areas in a prion-like way. Prions are infectious proteins which do not contain nucleic acids and cause diseases because they form toxic aggregates and filaments by misfolding in a ß-sheet-rich conformation. The misfolded protein behaves like a template inducing conformational change in the wild type proteins causing cross-reaction and leading to neurodegeneration. Later, the defective proteins may infect healthy nerve cells, thus neurodegeneration is extended. Growing experimental evidence shows that monomers and aggregates of α-synuclein are secreted via exocytosis from damaged nerve cells and taken up via endocytosis by healthy nerve cells furnishing evidence for the prion-like role of α-synuclein.