Missing pieces in the Parkinson's disease puzzle

Obeso, José A.; Rodriguez-Oroz, María C.; Goetz, Christopher G.; Marin, Concepcion A.; Kordower, Jeffrey H.; Rodrı́guez, Manuel; Hirsch, Étienne C.; Farrer, Matthew J.; Schapira, Anthony H.V.; Halliday, Glenda M.

doi:10.1038/nm.2165

Cited by 634 publications

(538 citation statements)

References 121 publications

Supporting

Mentioning

503

Contrasting

Unclassified

Order By: Relevance

“…This ability to preserve dopaminergic cells in animals with already established lesions is particularly significant for further clinical intervention since patients present motor symptoms once the nigrostriatal pathway has degenerated substantially. 45 Finally, and in agreement with the in vitro data, our results indicate that SC001 significantly reduced the accumulation of reactive microglia in the striatum of LPS-lesioned rats. Since administration of the endotoxin LPS in rats induces a robust glial activation and a subsequent dopaminergic cell loss that parallels many aspects of PD, 26,27 the data presented here suggest that, at least in part, the SC001 compound induces a protection of dopaminergic cells through anti-inflammatory mechanisms.…”

Section: ■ Conclusionsupporting

confidence: 90%

Glycogen Synthase Kinase-3 Inhibitors as Potent Therapeutic Agents for the Treatment of Parkinson Disease.

Morales-García

Susín

Alonso‐Gil

et al. 2012

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because the current therapies only lead to temporary, limited improvement and have severe side effects, new approaches to treat PD need to be developed. To discover new targets for potential therapeutic intervention, a chemical genetic approach involving the use of small molecules as pharmacological tools has been implemented. First, a screening of an in-house chemical library on a wellestablished cellular model of PD was done followed by a detailed pharmacological analysis of the hits. Here, we report the results found for the small heterocyclic derivative called SC001, which after different enzymatic assays was revealed to be a new glycogen synthase kinase-3 (GSK-3) inhibitor with IC 50 = 3.38 ± 0.08 μM. To confirm that GSK-3 could be a good target for PD, the evaluation of a set of structurally diverse GSK-3 inhibitors as neuroprotective agents for PD was performed. Results show that inhibitors of GSK-3 have neuroprotective effects in vitro representing a new pharmacological option for the disease-modifying treatment of PD. Furthermore, we show that SC001 is able to cross the blood−brain barrier, protects dopaminergic neurons, and reduces microglia activation in in vivo models of Parkinson disease, being a good candidate for further drug development.

show abstract

Section: ■ Conclusionsupporting

confidence: 90%

Glycogen Synthase Kinase-3 Inhibitors as Potent Therapeutic Agents for the Treatment of Parkinson Disease.

Morales-García

Susín

Alonso‐Gil

et al. 2012

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Agents currently under investigation are anti-apoptotics (Omigapil), anti-glutamatergics, monoamine oxidase inhibitors (Selegiline), promitochondrials (Coenzyme Q10, creatine), calcium channel blockers (Isradipine) and growth factors (GDNF). (9) A vaccine that primes the human immune system to destroy alpha-synuclein, PD01A (developed by Austrian company, Affairs), has entered clinical trials in humans. It has been proposed that effective treatments may be developed by use of induced pluripotent stem cells taken from adults.…”

Section: Futurementioning

confidence: 99%

“…(9) Cell death may be related to oxidative stress, protein aggregation but the mechanisms are not fully understood. …”

mentioning

confidence: 99%

Parkinson’s Disease- A Review

Krishna¹,

Prasad²,

Goel³

et al. 2018

jemds

View full text Add to dashboard Cite

“…Later, they appear in the substantia nigra, in some areas of the midbrain and basal forebrain, and finally in the neocortex (Davie 2008). In these places, there is neuronal degeneration, but it has been proposed that Lewy bodies could be a protection against harmful factors and not the cause of cell death (Obeso et al 2010;Schulz-Schaeffer 2010). However, in demented AD individuals, Lewy bodies are largely present in cortical areas and "reduced AS clearance is involved in the generation of AS inclusions in DLB and PD" (Brück et al 2015).…”

Section: Brain Neurons and Parkinson's Diseasementioning

confidence: 99%

Aging of perennial cells and organ parts according to the programmed aging paradigm

Libertini

Ferrara

2016

AGE

View full text Add to dashboard Cite

If aging is a physiological phenomenon-as maintained by the programmed aging paradigm-it must be caused by specific genetically determined and regulated mechanisms, which must be confirmed by evidence. Within the programmed aging paradigm, a complete proposal starts from the observation that cells, tissues, and organs show continuous turnover: As telomere shortening determines both limits to cell replication and a progressive impairment of cellular functions, a progressive decline in age-related fitness decline (i.e., aging) is a clear consequence. Against this hypothesis, a critic might argue that there are cells (most types of neurons) and organ parts (crystalline core and tooth enamel) that have no turnover and are subject to wear or manifest alterations similar to those of cells with turnover. In this review, it is shown how cell types without turnover appear to be strictly dependent on cells subjected to turnover. The loss or weakening of the functions fulfilled by these cells with turnover, due to telomere shortening and turnover slowing, compromises the vitality of the served cells without turnover. This determines well-known clinical manifestations, which in their early forms are described as distinct diseases (e.g., Alzheimer's disease, Parkinson's disease, age-related macular degeneration, etc.). Moreover, for the two organ parts (crystalline core and tooth enamel) without viable cells or any cell turnover, it is discussed how this is entirely compatible with the programmed aging paradigm.

show abstract

Missing pieces in the Parkinson's disease puzzle

Cited by 634 publications

References 121 publications

Glycogen Synthase Kinase-3 Inhibitors as Potent Therapeutic Agents for the Treatment of Parkinson Disease.

Glycogen Synthase Kinase-3 Inhibitors as Potent Therapeutic Agents for the Treatment of Parkinson Disease.

Parkinson’s Disease- A Review

Aging of perennial cells and organ parts according to the programmed aging paradigm

Contact Info

Product

Resources

About