Diagnosis and treatment of Parkinson disease: molecules to medicine - PubMed (original) (raw)

Review

Diagnosis and treatment of Parkinson disease: molecules to medicine

Joseph M Savitt et al. J Clin Invest. 2006 Jul.

Abstract

Parkinson disease (PD) is a relatively common disorder of the nervous system that afflicts patients later in life with tremor, slowness of movement, gait instability, and rigidity. Treatment of these cardinal features of the disease is a success story of modern science and medicine, as a great deal of disability can be alleviated through the pharmacological correction of brain dopamine deficiency. Unfortunately these therapies only provide temporary, though significant, relief from early symptoms and do not halt disease progression. In addition, pathological changes outside of the motor system leading to cognitive, autonomic, and psychiatric symptoms are not sufficiently treated by current therapies. Much as the discovery of dopamine deficiency led to powerful treatments for motor symptoms, recent discoveries concerning the role of specific genes in PD pathology will lead to the next revolution in disease therapy. Understanding why and how susceptible cells in motor and nonmotor regions of the brain die in PD is the first step toward preventing this cell death and curing or slowing the disease. In this review we discuss recent discoveries in the fields of diagnosis and treatment of PD and focus on how a better understanding of disease mechanisms gained through the study of monogenetic forms of PD has provided novel therapeutic targets.

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Figures

Figure 1. Model of dopaminergic cell death and possible sites for therapeutic intervention in PD.

Studies on inherited forms of PD have led to the identification of genes that, when mutated, lead to dopaminergic cell loss. These genes are involved in a variety of cellular processes that include protein ubiquitination and degradation via the proteasome, response to oxidative stress, protein phosphorylation, mitochondrial function, and protein folding. Potential points of therapeutic intervention are highlighted: gene silencing therapies to reduce synuclein levels (i); inhibitors of synuclein aggregation and/or processing (ii); interventions to downregulate toxic substrates or upregulate parkin or proteasomal function (iii); interventions to enhance mitochondrial function with factors such as CoQ10, DJ-1, or PINK-1 (iv); free radical scavengers and antioxidants (v); kinase inhibitors to block LRRK2 activity or interventions to increase PINK-1 function (vi); and other therapies using trophic factors such as GDNF, survival genes, or fetal/stem cell replacement that would protect or replace susceptible cells (vii).

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Diagnosis and treatment of Parkinson disease: molecules to medicine - PubMed (original) (raw)