Parkinson’s disease (PD) is an adult neurodegenerative disease affecting approximately 1% of the population over 65 years and 4%-5% over 80 years of age. The rate of disease progression is widely variable among subjects. PD is primarily a sporadic disease (about 90% of cases) (Rodriguez et al. 2015) while about 10% correspond to purely familial forms and have monogenic basis (Lesage and Brice 2009; Spataro et al. 2015). However, even within the sporadic form, some patients report genetic susceptibility factors, which are responsible for increasing the risk of developing PD. For instance, heterozygous mutations in GBA1 gene, encoding for the lysosomal enzyme glucocerebrosidase, have been detected in 5%-10% of sporadic PD patients (Sidransky et al. 2009; Schapira and Gegg 2013), thereby representing the most critical genetic risk factor in PD identified to date. PD is caused by the slow and progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNc); this leads to dopamine (DA) depletion of the corpus striatum followed by profound functional alterations of the basal ganglia circuitry, which controls the correct execution of voluntary movements (Blandini et al. 2000). In fact, PD is typically associated with motor symptoms, such as resting tremor, bradykinesia, slowness of movements, and postural instability. However, nonmotor symptoms are also present in PD patients and often precede the onset of classical motor manifestations (Olanow and Obeso 2012). These symptoms include olfactory impairment, sleep disorders, urogenital and gastrointestinal dysfunctions, and cognitive and psychiatric disturbances (Ferrer et al. 2012). Diagnosis of PD is performed on a clinical basis and can be confirmed only postmortem in patient brains, with the evidence of massive neuronal loss in the SNc and the detection of Lewy bodies (LBs), the main hallmark of PD. LBs are insoluble aggregates mainly containing α-synuclein, the protein encoded by SNCA or PARK1/PARK4 gene, a genetic locus linked to familial PD (Xu et al. 2015), as well as phosphorylated and poly-ubiquitinated proteins. Several lines of evidence clearly suggest that overexpression and oligomerization of α-synuclein are directly related to the toxicity in the nigrostriatal areas (Masliah et al. 2000; Hayashita-Kinoh et al. 2006). The presence of LBs is not restricted to SNc and other cerebral regions (Von Bohlen und Halbach et al. 2004); they also spread in the spinal cord, in the vagus nerve, and in peripheral organs such as the gastrointestinal tract (Beach et al. 2010), confirming that PD is a complex and diffuse disease, affecting not only the brain

Repurposing opportunities for Parkinson’s disease therapies

Ambrosi G.;Cerri S.;Blandini F.
2017

Abstract

Parkinson’s disease (PD) is an adult neurodegenerative disease affecting approximately 1% of the population over 65 years and 4%-5% over 80 years of age. The rate of disease progression is widely variable among subjects. PD is primarily a sporadic disease (about 90% of cases) (Rodriguez et al. 2015) while about 10% correspond to purely familial forms and have monogenic basis (Lesage and Brice 2009; Spataro et al. 2015). However, even within the sporadic form, some patients report genetic susceptibility factors, which are responsible for increasing the risk of developing PD. For instance, heterozygous mutations in GBA1 gene, encoding for the lysosomal enzyme glucocerebrosidase, have been detected in 5%-10% of sporadic PD patients (Sidransky et al. 2009; Schapira and Gegg 2013), thereby representing the most critical genetic risk factor in PD identified to date. PD is caused by the slow and progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNc); this leads to dopamine (DA) depletion of the corpus striatum followed by profound functional alterations of the basal ganglia circuitry, which controls the correct execution of voluntary movements (Blandini et al. 2000). In fact, PD is typically associated with motor symptoms, such as resting tremor, bradykinesia, slowness of movements, and postural instability. However, nonmotor symptoms are also present in PD patients and often precede the onset of classical motor manifestations (Olanow and Obeso 2012). These symptoms include olfactory impairment, sleep disorders, urogenital and gastrointestinal dysfunctions, and cognitive and psychiatric disturbances (Ferrer et al. 2012). Diagnosis of PD is performed on a clinical basis and can be confirmed only postmortem in patient brains, with the evidence of massive neuronal loss in the SNc and the detection of Lewy bodies (LBs), the main hallmark of PD. LBs are insoluble aggregates mainly containing α-synuclein, the protein encoded by SNCA or PARK1/PARK4 gene, a genetic locus linked to familial PD (Xu et al. 2015), as well as phosphorylated and poly-ubiquitinated proteins. Several lines of evidence clearly suggest that overexpression and oligomerization of α-synuclein are directly related to the toxicity in the nigrostriatal areas (Masliah et al. 2000; Hayashita-Kinoh et al. 2006). The presence of LBs is not restricted to SNc and other cerebral regions (Von Bohlen und Halbach et al. 2004); they also spread in the spinal cord, in the vagus nerve, and in peripheral organs such as the gastrointestinal tract (Beach et al. 2010), confirming that PD is a complex and diffuse disease, affecting not only the brain
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11571/1422854
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