Apoptosis in Parkinson's disease: Signals for neuronal degradation

Abstract

Despite being the subject of intense study, the pathogenesis of Parkinson's disease still remains unclear. In recent years, however, there has been increasing evidence to support a role for genetic factors in its cause. This has come from twin and family studies, the mapping and cloning of PARK genes that are associated with the development of PD, and analysis of potential susceptibility genes. There is also evidence indicating that environmental factors may play a role in the disease process. It is likely that for most cases, there is a complex interplay between these genetic and environmental influences in the causation of Parkinson's disease. This article reviews the evidence in support of genetic and environmental factors in the cause of PD.Ann Neurol 2003;53 (suppl 3):S16 -S25 Idiopathic Parkinson's disease (PD) is a common neurodegenerative condition characterized clinically by resting tremor, akinesia, and rigidity. The cause of the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta and the consequent depletion of dopamine in its striatal projections is unknown. Similarly, the pathogenetic relevance of the intracytoplasmic, ubiquitin-rich, eosinophilic inclusions (Lewy bodies) in the surviving dopaminergic neurons and other affected regions of the central nervous system is unclear, although their presence has been considered critical in making the pathological diagnosis of PD.

Apoptotic Mediators are Upregulated in the Skeletal Muscle of Chronic/Progressive Mouse Model of Parkinson's Disease

“…Previous studies have suggested the upregulation of p53 and active caspase-3 mediating apoptosis in the degenerating dopaminerbic neurons causing PD (Tatton, 2000;Tatton et al, 2003). Consistently, our analysis reveals the upregulation of p53 and active caspase-3 (Figs.…”

“…Apoptosis has been implicated in the pathogenesis of PD causing the degeneration of dopaminergic neurons (Mattson, 2000;Tatton, 2000;Tatton et al, 2003;Ekshyyan and Aw, 2004). Apoptosis is a programmed cell death that is mediated by a family of cysteine proteases called caspases (Sinkovics, 1991;Elmore, 2007;Ouyang et al, 2012).…”

“…Upregulation of the proapoptotic factors p53 and active caspase-3 has been shown in PD brains, suggesting the involvement of apoptosis in the pathogenesis of PD (Tatton, 2000;Tatton et al, 2003). Elevated levels of p53 and active caspase-3 have been reported in many muscular diseases, such as aging skeletal muscle and sarcopenia (Chung and Ng, 2006;Marzetti and Leeuwenburgh, 2006).…”

Mice overexpressing human caspase 3 appear phenotypically normal but exhibit increased apoptosis and larger lesion volumes in response to transient focal cerebral ischaemia

“…Caspase 3 has also been implicated in cell death following a number of neurodegenerative insults including global ischaemia, 12,13 focal ischaemia, [14][15][16][17][18][19] transient ischaemia of the spinal cord, 20 neonatal cerebral hypoxia-ischaemia, [21][22][23] traumatic brain injury, [24][25][26] Alzheimer's disease, [27][28][29] Huntington's disease, [30][31][32] and Parkinson's disease. [33][34][35][36][37] It was therefore hypothesized that overexpression of caspase 3 may sensitize the animal to normal (physiological) apoptotic processes that occur during development and natural ageing and confer particular susceptibility to neurodegenerative insults. To test this hypothesis, a caspase 3 transgenic mouse line was generated using a yeast artificial chromosome (YAC) containing the human genomic DNA spanning the full-length gene including all regulatory elements.…”

Finding the ‘Guilty’ Gene Variant of Sporadic Parkinson’s Disease Via CRISPR/Cas9

“…Most cases of PD are sporadic, possibly caused by complex interactions between common genetic and environmental risk factors [1], thus making it difficult to elucidate the exact pathogenic mechanisms.…”