Introduction session 10 Neurodegenerative diseases and ubiquitin-proteasome syster to copyright considerations See Figure chanover, A and Brundin, P. 2003. The ubiquitin proteasome enerative diseases: sometimes the chicken, sometimes the egg Neuron 40: The UPS and The figure describes four different aspects related to protein misfolding and neurodegenerative diseases (1)Triggers that can cause the accumulation of misfolded proteins-these include both mutations and epigenetic factors (2) The primary responses to accumulating misfolded proteins-these are related to the reduced capacity of the uPs that is the consequence of protein overload/inhibition by aggregated substrates, The misfolded proteins that accumulate may be refolded by chaperones or accumulate in aggregates in the cytoplasm, nucleus, or extracellular space, The aggregates may equester additional proteins 3)Types of neuropathological extracellular and intracellular protein deposits that can be found in the central nervous system of patients with PD, AD, Prion disease, ALS, and polyglutamine(Poly Q) disorders Finally, (4)four secondary disease targets, i.e., the different cell functions that are affected by ional disease. In different protein conformation disorders, it has been shown that gene transcription can be markedly disturbed at the levels of histone regulation and individual transcription factors. There is evidence for disrupted axonal transport of different cell constituents. At the presynaptic ansmitter synthesis can be impaired; vesicular storage is sometimes disrupted; proteins involved in vesicle cycling are altered. At the postsynaptic level, the misfolded proteins can change densities and downstream signaling transduction pathways, Finally, the diseases can ause neuronal death by several mechanisms, including impairment of mitochondrial function and mitochondrial release of ytochrome c with subsequent caspase activation. It has also been suggested that aberrant protein folding can lead to pore formation in cell membranes and loss of ionic homeostasis Parkinson's disease(PD described in various rare forms of hereditary PD that shed light on basic pathogenic In PD, the main neuropathological feature is mechanisms that maybe relevant also to the the progressive death of neurons in the most prevalent late-onset and sporadic cases substantia nigra pars compacta with resulting loss of dopaminergic innervation of the striatum. This causes a gradual An important player in the pathogenesis of PD development of akinesia, rigidity, and is Parkin (PARK2). Parkin is a protein with a tremor In the vast majority of patients, some UBL domain at the N-terminal region and two of the remaining nigral dopaminergic neurons RING finger motifs at the carboxy-terminc exhibit aggregated proteins in the form of region, identified as an ubiquitin- E3 ligase cytoplasmic LB (Lewy Body) inclusions that acts along with the ubiquitin-conjugating Several apparently independent aberrations enzymes UbcH7 and UbcH8, Various delet linked to defects in the ups have been and point mutations in the gene have beenIntroduction Session 10 “Neurodegenerative diseases and ubiquitin-proteasome system” Image removed due to copyright considerations. See Figure 2 in Ciechanover, A. and Brundin, P. 2003. The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40: 427-446. The UPS and Pathogenesis of Neurodegeneration The figure describes four different aspects related to protein misfolding and neurodegenerative diseases: (1) Triggers that can cause the accumulation of misfolded proteins—these include both mutations and epigenetic factors. (2) The primary responses to accumulating misfolded proteins—these are related to the reduced capacity of the UPS that is the consequence of protein overload/inhibition by aggregated substrates. The misfolded proteins that accumulate may be refolded by chaperones or accumulate in aggregates in the cytoplasm, nucleus, or extracellular space. The aggregates may sequester additional proteins. (3) Types of neuropathological extracellular and intracellular protein deposits that can be found in the central nervous system of patients with PD, AD, Prion disease, ALS, and polyglutamine (PolyQ) disorders. Finally, (4) four secondary disease targets, i.e., the different cell functions that are affected by the protein conformational disease. In different protein conformation disorders, it has been shown that gene transcription can be markedly disturbed at the levels of histone regulation and individual transcription factors. There is evidence for disrupted axonal transport of different cell constituents. At the presynaptic level, neurotransmitter synthesis can be impaired; vesicular storage is sometimes disrupted; proteins involved in vesicle cycling are altered. At the postsynaptic level, the misfolded proteins can change receptor densities and downstream signaling transduction pathways. Finally, the diseases can cause neuronal death by several mechanisms, including impairment of mitochondrial function and mitochondrial release of cytochrome c with subsequent caspase activation. It has also been suggested that aberrant protein folding can lead to pore formation in cell membranes and loss of ionic homeostasis. Parkinson’s disease (PD) In PD, the main neuropathological feature is the progressive death of neurons in the substantia nigra pars compacta with resulting loss of dopaminergic innervation of the striatum. This causes a gradual development of akinesia, rigidity, and tremor. In the vast majority of patients, some of the remaining nigral dopaminergic neurons exhibit aggregated proteins in the form of cytoplasmic LB (Lewy Body) inclusions. Several apparently independent aberrations linked to defects in the UPS have been described in various rare forms of hereditary PD that shed light on basic pathogenic mechanisms that maybe relevant also to the most prevalent late-onset and sporadic cases of PD. An important player in the pathogenesis of PD is Parkin (PARK2). Parkin is a protein with a UBL domain at the N-terminal region and two RING finger motifs at the carboxy-terminal region, identified as an ubiquitin- E3 ligase that acts along with the ubiquitin-conjugating enzymes UbcH7 and UbcH8. Various deletion and point mutations in the gene have been