Genetic Forms Of Parkinson's Disease Research Articles

Parkin gene therapy

The search for genetic mutations responsible for familial forms of Parkinson's disease (PD) has identified several genes and loci. Mutations in the parkin gene are linked to autosomal recessive juvenile parkinsonism. The genetic forms of PD are uncommon, but gene therapy targeting α-synuclein, parkin, or other pathways may be also applicable for idiopathic PD. Intriguingly, several studies suggest that parkin gene therapy could be useful in a subset of PD patients with mutations in the α-synuclein gene. Furthermore, if parkin overexpression can correct neuronal degeneration in the substantia nigra and striatum, it might be a potentially effective therapy for α-synucleinopathy.

Invited Article: Functional imaging in Parkinson disease

Functional imaging techniques represent useful tools to assess in vivo the neurochemical alterations and functional connectivity in Parkinson disease (PD). Here, the authors review the various approaches and potential application of these imaging techniques to the study of PD. Radiotracer imaging using dopaminergic markers facilitates assessment of pre- and postsynaptic nigrostriatal integrity, while imaging with other appropriate radiotracers explores nondopaminergic neurotransmitter function, local metabolism, blood flow, and mechanisms potentially related to disease progression and pathogenesis. Activation studies using functional MRI detect blood oxygen level dependent signal, as an indirect marker of neuronal activity. Functional imaging techniques have been applied to infer the potential role of inflammation and other factors in etiopathogenesis as well as to study compensatory and regulatory mechanisms in early PD and subclinical disease in genetic forms of PD. Imaging studies also help to understand the neurobiological basis of motor and nonmotor complications. Recent reports suggest a role for striatal dopaminergic transmission in modulating neurobehavioral processes including the placebo effect in PD. Although functional imaging has been employed to monitor disease progression, the discordance between clinical outcome and imaging measures after therapeutic interventions precludes their use as surrogate end points in clinical trials. Beyond these limitations and potential challenges, imaging techniques continue to find wide application in the study of PD. Functional imaging can provide meaningful insights into mechanisms underlying various aspects of motor and nonmotor dysfunction in Parkinson disease and the role of striatal dopaminergic transmission in behavioral processes beyond motor control. These modalities hold promise to study the preclinical phase and to elucidate further the benefits and complications of surgical interventions and the utility of neuroprotective strategies.

Modulation of microglial pro-inflammatory and neurotoxic activity for the treatment of Parkinson’s disease

Parkinson's disease (PD) is a debilitating movement disorder resulting from a progressive degeneration of the nigrostriatal dopaminergic pathway and depletion of neurotransmitter dopamine in the striatum. Molecular cloning studies have identified nearly a dozen genes or loci that are associated with small clusters of mostly early onset and genetic forms of PD. The etiology of the vast majority of PD cases remains unknown, and the precise molecular and biochemical processes governing the selective and progressive degeneration of the nigrostriatal dopaminergic pathway are poorly understood. Current drug therapies for PD are symptomatic and appear to bear little effect on the progressive neurodegenerative process. Studies of postmortem PD brains and various cellular and animal models of PD in the last 2 decades strongly suggest that the generation of pro-inflammatory and neurotoxic factors by the resident brain immune cells, microglia, plays a prominent role in mediating the progressive neurodegenerative process. This review discusses literature supporting the possibility of modulating the activity of microglia as a neuroprotective strategy for the treatment of PD.

Caspase-3-derived C-terminal Product of Synphilin-1 Displays Antiapoptotic Function via Modulation of the p53-dependent Cell Death Pathway

Parkinson disease is the second most frequent neurodegenerative disorder after Alzheimer disease. A subset of genetic forms of Parkinson disease has been attributed to alpha-synuclein, a synaptic protein with remarkable chaperone properties. Synphilin-1 is a cytoplasmic protein that has been identified as a partner of alpha-synuclein (Engelender, S., Kaminsky, Z., Guo, X., Sharp, A. H., Amaravi, R. K., Kleiderlein, J. J., Margolis, R. L., Troncoso, J. C., Lanahan, A. A., Worley, P. F., Dawson, V. L., Dawson, T. M., and Ross, C. A. (1999) Nat. Gen. 22, 110-114), but its function remains totally unknown. We show here for the first time that synphilin-1 displays an antiapoptotic function in the control of cell death. We have established transient and stable transfectants overexpressing wild-type synphilin-1 in human embryonic kidney 293 cells, telecephalon-specific murine 1 neurons, and SH-SY5Y neuroblastoma cells, and we show that both cell systems display lower responsiveness to staurosporine and 6-hydroxydopamine. Thus, synphilin-1 reduces procaspase-3 hydrolysis and thereby caspase-3 activity and decreases poly(ADP-ribose) polymerase cleavage, two main indicators of apoptotic cell death. Furthermore, we establish that synphilin-1 drastically reduces p53 transcriptional activity and expression and lowers p53 promoter transactivation and mRNA levels. Interestingly, we demonstrate that synphilin-1 catabolism is enhanced by staurosporine and blocked by caspase-3 inhibitors. Accordingly, we show by transcription/translation assay that recombinant caspase-3 and, to a lesser extent, caspase-6 but not caspase-7 hydrolyze synphilin-1. Furthermore, we demonstrate that mutated synphilin-1, in which a consensus caspase-3 target sequence has been disrupted, resists proteolysis by cellular and recombinant caspases and displays drastically reduced antiapoptotic phenotype. We further show that the caspase-3-derived C-terminal fragment of synphilin-1 was probably responsible for the antiapoptotic phenotype elicited by the parent wild-type protein. Altogether, our study is the first demonstration that synphilin-1 harbors a protective function that is controlled by the C-terminal fragment generated by its proteolysis by caspase-3.

Genetics of Parkinson's disease

The etiology of most cases of Parkinson's disease (PD) remains unknown. In recent years, however, research has successfully focused on genetic factors contributing to the degeneration of dopaminergic neurons. Causative mutations have been identified in several monogenically inherited forms of the disease. Although these genetic forms of PD are usually rare, the gene discoveries are likely to identify molecular pathways that are also relevant in the sporadic disorder. These studies have led to the identification of (i) the central role of α-synuclein aggregation, secondary to either point mutations or an amplification of the α-synuclein gene; and (ii) the relevance of defects in the proteasomal protein degradation pathway in the molecular pathogenesis of recessive parkin-linked forms of PD. The recent discoveries of two additional recessive forms associated with mutations in the genes DJ-1 and PINK1 have brought the mitochondrial energy metabolism and the cell's defence against toxic free radicals into the focus of research.

Etiology of Parkinson's disease: Genetics and environment revisited.

Idiopathic Parkinson's disease (PD) is the second most common neurodegenerative disorder and affects more than 1 million Americans over the age of 55. The disease selectively affects dopaminergic neurons of the substantia nigra pars compacta, culminating in their demise. After ≈50% of the dopamine neurons and 75–80% of striatal dopamine is lost, patients start to exhibit the classical symptoms of PD including bradykinesia, postural reflex impairment, resting tremor, and rigidity (1, 2). Although there are several treatments that are effective for a number of years, their usefulness wanes over time and is accompanied by unacceptable side effects. New therapies are clearly needed for this disorder. Despite many years of focused research, the causes of this disease remain to be elucidated. Understanding the cause of PD is critical as that knowledge could lead to directed research that will develop new and potent therapies. The relative contributions of genetic versus environmental factors regarding the cause of PD have been hotly debated. In an attempt to define a cause for this disease, early epidemiological studies examining twins suggested an absence of genetic factors (3). However, these studies were not definitive and could never account for differences in disease progression between twin pairs that could account for discordance in diagnosis. The discovery that the protoxin n -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in both humans and nonhumans further strengthened the hypothesis that PD had an environmental etiology. Other environmental toxins have been shown to induce a parkinsonian state as well, supporting this view (4). However, the recent discovery of inherited forms of PD shifted the emphasis back to genetic factors. Among the different genetic forms of PD, mutations in the gene encoding for α-synuclein have received the most attention. Mutations in this gene cause rare forms of PD. Furthermore, α-synuclein is also present in the …