Progress toward an integrated understanding of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting over 10 million individuals worldwide. While numerous effective symptomatic treatments are currently available, no curative or disease-modifying therapies exist. An integrated, comprehensive understanding of PD pathogenic mechanisms will likely address this unmet clinical need. Here, we highlight recent progress in PD research with an emphasis on promising translational findings, including (i) advances in our understanding of disease susceptibility, (ii) improved knowledge of cellular dysfunction, and (iii) insights into mechanisms of spread and propagation of PD pathology. We emphasize connections between these previously disparate strands of PD research and the development of an emerging systems-level understanding that will enable the next generation of PD therapeutics.

Dopamine Modulates Serotonin Innervation in the Drosophila Brain

“…A small minority of PD cases are linked to pathogenic gene mutations responsible for the development of the disease. However, studies of rare Mendelian forms of PD allowed for the identification of more than 20 PD genes and variants that are implicated in its development (Rousseaux et al, 2017 ). Whereas, about 10–15 percent of Parkinson’s patients are thought to suffer from a genetic form of this dystonic movement disorder, most patients suffer from a sporadic form of PD most likely resulting from a combination of environmental factors and undefined individual genetic susceptibility (Obeso et al, 2014 ; Ascherio and Schwarzschild, 2016 ).…”

Pathogenesis‐targeted therapeutic strategies in Parkinson's disease

“…These include specific approaches designed to correct certain aspects of dysfunction in the autophagylysosomal and mitochondrial processes, postulated to play a role in neurodegeneration associated with PD. [23][24][25] Because many pathogenic mechanisms play a role in neuronal cell death associated with PD, it is likely that any disease-modifying strategy will require multiple approaches targeting various dysfunctional pathways involved in the disease process. Although one final common pathway may underly apoptosis, there are many different upstream pathogenic mechanisms that may be specific or unique for the different subtypes of PD.…”

“…Coupled with advances in the symptomatic therapeutics of PD, 27,28 the disease-modifying strategies described in this review offer a promise of a brighter and more hopeful future for patients with PD. E. Decrease α-synuclein expression: salbutamol and clenbuterol (β2-adrenoreceptor agonists) 33 Genetically determined therapies 21,22 F. Inhibition of LRRK2 kinase activity in patients with LRRK2 mutation Small molecules DNL201 or DNL151 (Denali Therapeutics Inc.) -LRRK2 kinase inhibitor successfully tested in phase 1 study (there are concerns about renal, pulmonary, long-term toxicity) 34 G. Upregulation of glucocerebrosidase (GCase) in subjects with GBA gene mutation 23 GZ/SAR402671glucosylceramide synthase inhibitor, GBA enhancer in patients with early-stage PD carrying a GBA mutation (MOVES-PD -Sanofi/Genzyme); NCT02906020…”

“…Other cellular therapeutic targets 6,23 Altered calcium homeostasis (increased CaV1.3 channel expression)…”

“…Autophagic dysfunctionsirolimus, trehalose (induction of autophagosome biogenesis), MSDC-0160, retinoic acid derivatives, enhance transcription factor EB by beta-cyclodextrins or by genetic overexpression 6,31,39,40 Lysosomal dysfunction -NCGC758 and NCGC607 6,23,31 Mitochondrial dysfunction -EPI-589 ((NCT02462603) 32,39,40 Neuroinflammationautologous adipose-derived stromal stem cells (NCT01453803) 32,39,40 Movement Disorders, Vol. 34…”