Cell death mechanisms in neurodegeneration

Abstract

Progressive cell loss in specific neuronal populations often associated with typical cytoskeletal protein aggregations is a pathological hallmark of neurodegenerative disorders, but the nature, time course and molecular causes of cell death and their relation to cytoskeletal pathologies are still unresolved. Apoptosis or alternative pathways of cell death have been discussed in Alzheimer's disease and other neurodegenerative disorders. Apoptotic DNA fragmentation in human brain as a sign of neuronal injury is found too frequent as to account for continous neuron loss in these slowly progressive processes. Morphological studies revealed extremely rare apoptotic neuronal death in Alzheimer's disease but yielded mixed results for Parkinson's disease and other neurodegenerative disorders. Based on recent data in human brain, as well as in animal and cell culture models, a picture is beginning to emerge suggesting that, in addition to apoptosis, other forms of programmed cell death may participate in neurodegeneration. Better understanding of the molecular players will further elucidate the mechanisms of cell death in these disorders and their relations to cytoskeletal abnormalities. Susceptible cell populations in a proapoptotic environment show increased vulnerability towards multiple noxious factors discussed in the pathogenesis of neurodegeneration. In conclusion, although many in vivo and in vitro data are in favor of apoptosis involvement in neurodegenerative processes, there is considerable evidence that very complex events may contribute to neuronal death with possible repair mechanisms, the elucidation of which may prove useful for future prevention and therapy of neurodegenerative disorders.

Specificity and Kinetics of α-Synuclein Binding to Model Membranes Determined with Fluorescent Excited State Intramolecular Proton Transfer (ESIPT) Probe

“…For an initial comparison of the AS binding rates to membranes of different composition, we determined a pseudo-first-order reaction rate constant measured at 0.25 M protein and 50 M lipid concentrations. Negatively charged SUVs interacted with AS in the 1-20 ms range, consistent with the reported AS exchange rate in SDS micelles (10 ms) measured by 19 F NMR (62). The binding to neutral SUVs was much slower, in the range of seconds, and the reaction rates and binding affinities were not linearly related ( Table 1).…”

“…Furthermore, AS-membrane interactions have been reported to play a role in Parkinson disease pathology (16,18,19). For example, there is compelling evidence suggesting that low molecular AS aggregates or oligomers disrupt membranes and/or induce the formation of ion channels (20,21), possibly leading to cellular and mitochondrial membrane depolarization (22).…”

Beyond antioxidants: the cellular and molecular interactions of flavonoids and how these underpin their actions on the brain

“…In contrast, the inhibition afforded by flavanones, such as hesperetin, is not accompanied by the formation of cysteinyl-hesperetin adducts, indicating that it may inhibit via direct interaction with tyrosinase (132) . Reactive oxygen and nitrogen species have also been proposed to play a role in the pathology of many neurodegenerative diseases (113) (Fig. 3).…”

“…The underlying neurodegeneration observed in Parkinson's disease, Alzheimer's disease, and other neurodegenerative diseases is believed to be triggered by multi-factorial processes, including neuroinflammation, glutamatergic excitotoxicity, increases in Fe and/or depletion of endogenous antioxidants (112)(113)(114) . There is a growing body of evidence to suggest that flavonoids and other polyphenols may be able to counteract this neuronal injury, thereby delaying the progression of these brain pathologies (1,46,(115)(116)(117)(118)(119) .…”

Significance of Retinoblastoma Protein in Survival and Differentiation of Cerebellar Neurons

“…Many neurological diseases such as Alzheimer's, tauopathies, Parkinson's etc., show neuronal loss in specific areas of the brain (Burke, 1998;Cotman and Anderson, 1995;Cotman and Su, 1996;Forloni, 1993;Gorman et al, 1996;Hajimohamadreza and Treherne, 1997;Hartmann and Hirsch, 2001;Honig and Rosenberg, 2000;Jellinger, 2001;Savitz and Rosenbaum, 1998;Yanagisawa, 2000;Yuan and Yankner, 2000). Although a number of signaling pathways have been implicated in the apoptosis observed in the brains it is difficult to determine whether inhibition of these pathways has any effect on neuronal survival in vivo.…”