Biology Reference
In-Depth Information
resting tremor, difficulty initiating movements, and postural instability but it is
also becoming recognized that nonmotor symptoms, including autonomic and
cognitive disturbances, are an integral part of the disease. Although there are
signs of pathology in many brain regions, the motor symptoms are largely
attributable to the selective degeneration of dopaminergic (DA) neurons in
the substantia nigra pars compacta (Forno, 1996). The mainstay of therapeutic
intervention, DA replacement treatment by levodopa (L-DOPA) can, for a time,
substitute for the lost striatal DA innervation and effectively ameliorate the
motor symptoms. However, the nonmotor symptoms are likely to have a different
pathological basis and are largely refractory to DA drugs (Poewe, 2009). “Pure”
PD is also characterized pathologically by the presence of intraneuronal inclu-
sions called Lewy bodies and Lewy neurites.
The majority of cases occur sporadically; hence, it is generally consid-
ered that a combination of both genetic susceptibility and environmental factors
plays a role in the pathogenic cause. Identification of those causative factors is, of
course, paramount in the pursuit of a disease-modifying therapy. While the
precise pathologic mechanisms remain unclear, epidemiological and genetic
studies have begun to yield insights into putative pathogenic causes. Currently,
the commonly favored mechanisms include aberrant protein degradation, mito-
chondrial dysfunction, calcium imbalance, and inflammation (Gupta
,
2008). In addition, oxidative stress is a prominent and common feature in all
forms of PD and likely represents a convergent toxic event leading to neuronal
cell death. It is still unclear whether experimentally induced defects, observed in
either genetic or toxin models, represent nodal junctures suitable for therapeutic
targeting. Indeed, it is also unclear whether these observed defects are common
across the spectrum of Parkinsonism disorder. However, the pursuit of mecha-
nism-based studies in experimentally tractable model systems still likely presents
the best route toward a tailored disease-modifying therapy.
Definitive evidence for environmental factors in sporadic cases has
remained relatively elusive; however, the evidence for the influence of genetic
contribution has been accelerating (Gasser, 2009). In a little over a decade,
linkage studies have begun to identify single-gene mutations responsible for rare
heritable forms of PD which in many cases is clinically indistinguishable from the
more common sporadic cases, with the exception of early onset. While this
approach is technically advantageous, to be applicable to all forms of PD, it
assumes a shared pathogenic mechanism between inherited and sporadic cases.
To identify genetic susceptibility factors for sporadic PD, the incredible techni-
cal advances in robust genome-wide methodologies have allowed interrogation
of thousands of disease and control samples to potentially correlate disease with
commonly occurring polymorphisms. Genome-wide association studies
(GWAS) have revealed susceptibility risk for a relatively small set of genes
(reviewed by Gandhi and Wood, 2010). Encouragingly, these included genes
et al.
