Aggregation of the nerve cell protein ␣-synuclein is a characteristic of the common neurodegenerative ␣-synucleinopathies like Parkinson's disease and Lewy body dementia, and it plays a direct pathogenic role as demonstrated by early onset diseases caused by missense mutations and multiplication of the ␣-synuclein gene. We investigated the existence of ␣-synuclein proaggregatory brain proteins whose dysregulation may contribute to disease progression, and we identified the brain-specific p25␣ as a candidate that preferentially binds to ␣-synuclein in its aggregated state. Functionally, purified recombinant human p25␣ strongly stimulates the aggregation of ␣-synuclein in vitro as demonstrated by thioflavin-T fluorescence and quantitative electron microscopy. p25␣ is normally only expressed in oligodendrocytes in contrast to ␣-synuclein, which is normally only expressed in neurons. This expression pattern is changed in ␣-synucleinopathies. In multiple systems atrophy, degenerating oligodendrocytes displayed accumulation of p25␣ and dystopically expressed ␣-synuclein in the glial cytoplasmic inclusions. In Parkinson's disease and Lewy body dementia, p25␣ was detectable in the neuronal Lewy body inclusions along with ␣-synuclein. The localization in ␣-synuclein-containing inclusions was verified biochemically by immunological detection in Lewy body inclusions purified from Lewy body dementia tissue and glial cytoplasmic inclusions purified from tissue from multiple systems atrophy. We suggest that p25␣ plays a pro-aggregatory role in the common neurodegenerative disorders hallmarked by ␣-synuclein aggregates.The group of ␣-synucleinopathies is dominated by the frequent neurodegenerative disorders Parkinson's disease (PD), 1 Lewy body dementia (LBD), a Lewy body variant of Alzheimer's disease, and multiple system atrophy (MSA) (1-4). Their unifying hallmark is the development of aggregates of the 140-amino acid ␣-synuclein (AS) protein, which is deposited in intracellular inclusions. The inclusions comprise the Lewy body-type of inclusions in the neuronal cell body, the Lewy neurites in axons, and the oligodendrocytic glial cytoplasmic inclusions in MSA. AS can play an active role in the degenerative processes as evidenced by studies of families with autosomal dominant early onset PD and LBD caused by missense mutations in the AS gene (5-7) and the overexpression of the wild type protein caused by gene multiplications of the AS locus (8 -10). However, the role of AS in the sporadic diseases is less clear. The frequency of AS aggregation in human diseases has given rise to extensive studies of the process in vitro. These studies have revealed that this aggregation represents a nucleation-dependent process (11). The transition from monomeric AS to filamentous aggregates is characterized by a lag phase during which a build-up of soluble nucleation-competent oligomeric AS species takes places. The rapid filament growth does not occur until these structures have reached a critical concentration. This process is stimulated...

p25alpha is an oligodendroglial protein that can induce aggregation of alpha-synuclein and accumulates in oligodendroglial cell bodies containing fibrillized alpha-synuclein in the neurodegenerative disease multiple system atrophy (MSA). We demonstrate biochemically that p25alpha is a constituent of myelin and a high-affinity ligand for myelin basic protein (MBP), and in situ immunohistochemistry revealed that MBP and p25alpha colocalize in myelin in normal human brains. Analysis of MSA cases reveals dramatic changes in p25alpha and MBP throughout the course of the disease. In situ immunohistochemistry revealed a cellular redistribution of p25alpha immunoreactivity from the myelin to the oligodendroglial cell soma, with no overall change in p25alpha protein concentration using immunoblotting. Concomitantly, an approximately 80% reduction in the concentration of full-length MBP protein was revealed by immunoblotting along with the presence of immunoreactivity for MBP degradation products in oligodendroglia. The oligodendroglial cell bodies in MSA displayed an enlargement along with the relocalization of p25alpha, and this was enhanced after the deposition of alpha-synuclein in the glial cytoplasmic inclusions. Overall, the data indicate that changes in the cellular interactions between MBP and p25alpha occur early in MSA and contribute to abnormalities in myelin and subsequent alpha-synuclein aggregation and the ensuing neuronal degeneration that characterizes this disease.

Reactive oxygen species (ROS) can be both beneficial and deleterious. Under normal physiological conditions, ROS production is tightly regulated, and ROS participate in both pathogen defense and cellular signaling. However, insufficient ROS detoxification or ROS overproduction generates oxidative stress, resulting in cellular damage. Oxidative stress has been linked to various inflammatory diseases. Inflammation is an essential response in the protection against injurious insults and thus important at the onset of wound healing. However, hampered resolution of inflammation can result in a chronic, exaggerated response with additional tissue damage. In the pathogenesis of several inflammatory skin conditions, e.g., sunburn and psoriasis, inflammatory-mediated tissue damage is central. The prolonged release of excess ROS in the skin can aggravate inflammatory injury and promote chronic inflammation. The cellular redox balance is therefore tightly regulated by several (enzymatic) antioxidants and pro-oxidants; however, in case of chronic inflammation, the antioxidant system may be depleted, and prolonged oxidative stress occurs. Due to the central role of ROS in inflammatory pathologies, restoring the redox balance forms an innovative therapeutic target in the development of new strategies for treating inflammatory skin conditions. Nevertheless, the clinical use of antioxidant-related therapies is still in its infancy.

Development in the central nervous system is highly dependent on the regulation of the switch from progenitor cell proliferation to differentiation, but the molecular and cellular events controlling this process remain poorly understood. Here, we report that ablation of Crb1 and Crb2 genes results in severe impairment of retinal function, abnormal lamination and thickening of the retina mimicking human Leber congenital amaurosis due to loss of CRB1 function. We show that the levels of CRB1 and CRB2 proteins are crucial for mouse retinal development, as they restrain the proliferation of retinal progenitor cells. The lack of these apical proteins results in altered cell cycle progression and increased number of mitotic cells leading to an increased number of late-born cell types such as rod photoreceptors, bipolar and Müller glia cells in postmitotic retinas. Loss of CRB1 and CRB2 in the retina results in dysregulation of target genes for the Notch1 and YAP/Hippo signaling pathways and increased levels of P120-catenin. Loss of CRB1 and CRB2 result in altered progenitor cell cycle distribution with a decrease in number of late progenitors in G1 and an increase in S and G2/M phase. These findings suggest that CRB1 and CRB2 suppress late progenitor pool expansion by regulating multiple proliferative signaling pathways.