Elsevier

The Lancet

Volume 384, Issue 9942, 9–15 August 2014, Pages 545-555
The Lancet

Series
Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives

https://doi.org/10.1016/S0140-6736(14)61010-2Get rights and content

Summary

Several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease and Huntington's disease. These advances have been informed by both direct analysis of the post-mortem brain and by study of the biological consequences of the genetic causes of these diseases. Some of the pathways that have been implicated so far include mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, inflammation, protein handling, and prion-like processes. Intriguingly, these pathways seem to be important in the pathogenesis of both diseases and have led to the identification of molecular targets for candidate interventions designed to slow or reverse their course. We review some recent advances that underlie putative therapies for neuroprotection in Parkinson's disease and Huntington's disease, and potential targets that might be exploited in the future. Although we will need to overcome important hurdles, especially in terms of clinical trial design, we propose several target pathways that merit further study. In Parkinson's disease, these targets include agents that might improve mitochondrial function or increase degradation of defective mitochondria, kinase inhibitors, calcium channel blockers, and approaches that interfere with the misfolding, templating, and transmission of α-synuclein. In Huntington's disease, strategies might also be directed at mitochondrial bioenergetics and turnover, the prevention of protein dysregulation, disruption of the interaction between huntingtin and p53 or huntingtin-interacting protein 1 to reduce apoptosis, and interference with expression of mutant huntingtin at both the nucleic acid and protein levels.

Introduction

Parkinson's disease is a common neurodegenerative disorder with an age-adjusted incidence of 13·5–13·9 per 100 000 person-years and an age-related prevalence of roughly 115 per 100 000 population. The frequency of the disorder is about 1·3 cases per 100 000 people younger than 45 years of age, 3100 per 100 000 in those aged 75–85 years, and 4300 per 100 000 in those older than 85 years.1 Although existing treatments provide benefit for the dopaminergic features of the disease, disability in patients with advanced disease is mostly related to non-dopaminergic features, such as falling, freezing, and dementia, which are not controlled adequately with dopaminergic therapies.

Huntington's disease is a neurodegenerative genetic disorder with a prevalence of 5–10 cases per 100 000 people worldwide, with regional variations.2 The rate of occurrence is highest in people of western European descent (with the exception of the highest regional prevalence around Lake Maracaïbo, Venezuela)3 with, for example, a prevalence of 12·3 per 100 000 people in the UK,4 and a lower frequency in the rest of the world (eg, one per million people of Asian and African descent). At present, management of the disease is limited to a few treatment options in the early stages for the control of the hyperkinetic movement disorders and psychiatric problems, but no treatment modifies the course of the disease.5

In both Parkinson's disease and Huntington's disease, neurodegeneration is progressive and leads to severe disability and reduced quality of life and life expectancy. Treatments that slow or prevent disease progression in both disorders are a major unmet need. Recent scientific advances have identified new pathways in these diseases that suggest new targets for the development of neuroprotective drugs. In this review, we will summarise some of the most promising candidate targets for neuroprotection. Please see appendix for a list of supplementary references.

Section snippets

Challenges and solutions: Parkinson's disease

Several drugs exist for the symptomatic relief of the dopaminergic motor features in Parkinson's disease (figure 1). Nonetheless, disease progression is inexorable, and patients ultimately develop disability, which is largely related to the development of non-dopaminergic features such as gait disturbance and dementia. A crucial goal is the development of a neuroprotective treatment that slows disease progression and has beneficial effects on the full range of dopaminergic and non-dopaminergic

Challenges and solutions: Huntington's disease

Unlike Parkinson's disease, no major treatment has been developed specifically for Huntington's disease. Some symptomatic treatment is available for some motor or psychiatric features. The cause of Huntington's disease is a highly polymorphic CAG trinucleotide repeat expansion in exon 1 of the gene encoding the huntingtin protein.11 By contrast with Parkinson's disease, neuroprotective strategies could be available immediately for carriers of mutant huntingtin identified by genetic testing in

Targets for neuroprotection

Several exciting potential targets for drug intervention to lessen neurodegeneration in both Parkinson's disease and Huntington's disease are in development. Some of these targets are single molecules, whereas others involve the manipulation of biochemical pathways and several genes or proteins. Different approaches might be applicable at different stages of the disease and in different populations (figure 3). For example, primary prevention will be appropriate for the molecular prodrome, which

Mitochondrial function and oxidative stress pathways

Evidence suggests that defects of the respiratory chain (complex I), increased accumulation of mitochondrial DNA mutations, abnormal mitochondrial calcium homoeostasis, defective autophagic removal of mitochondria (mitophagy), and increased oxidative stress are all involved in the pathogenesis of Parkinson's disease.15 Previous attempts to intervene in some of these pathways for mitochondrial diseases have failed or have provided only little benefit. We will focus on some of the approaches that

Calcium handling

Calcium homoeostasis, receptor activity, and calcium-evoked oxidative stress are recognised as potential contributors to the pathogenesis of Parkinson's disease and potential targets for therapeutic intervention.37 Evidence suggests that over time, pacing of nigral dopaminergic neurons converts from reliance on sodium channels to L-type calcium channels (Ca[v]1·3) to maintain autonomous activity. This dependence can be reversed, and protection against toxin-induced damage achieved, by the

Kinase pathways

Several observations indicate that phosphorylation pathways are important in the pathogenesis of Parkinson's disease and might be suitable targets for drug development. α-synuclein can undergo phosphorylation at several sites; phosphorylation at serine 129 constitutes the major form of the protein in Lewy bodies.41 The Ala53Thr α-synuclein mutation, which causes familial Parkinson's disease, increases the amount of S-129 phosphorylation. S-129 phosphorylation of α-synuclein reportedly enhances

Parkinson's disease

Targeting of the formation and clearance of unwanted proteins is another logical approach to the development of a candidate neuroprotective therapy for Parkinson's disease, since the disease is characterised by the accumulation of aggregated proteins in the form of Lewy bodies and Lewy neurites. Protein accumulation could result from increased production or impaired clearance. Unwanted proteins are usually cleared from the cell by the ubiquitin proteasome or autophagy–lysosomal systems, and

Trophic factors

Trophic factors are proteins that act on membrane receptors to activate protective signals (eg, phosphoinositide 3-kinase/Akt and extracellular-signal-regulated kinase) and promote cell growth and viability. The GDNF family of trophic factors, which act on both receptor tyrosine kinase (RET) and GFRα receptors, have been studied in Parkinson's disease on the basis of their capacity in laboratory models to protect dopamine neurons from a range of toxins or restore function even when administered

Counteracting apoptosis in Huntington's disease

Although apoptosis is potentially a terminal pathway relevant to both Parkinson's disease and Huntington's disease, recent evidence suggests the value of targeting of pro-apoptotic pathways in Huntington's disease—an approach that has been somewhat abandoned for Parkinson's disease, especially since the failure of strategies such as CEP-1347, a semi-synthetic inhibitor of the mixed lineage kinase family.104 Neuronal cell death in Huntington's disease is associated with neuronal apoptosis, in

Conclusion

Despite the many therapeutic advances in Parkinson's disease and Huntingtin's disease, affected patients eventually experience intolerable disability and early death. A neuroprotective therapy that slows or stops disease progression and prevents the development of cumulative disability remains the highest priority in drug development. Although no agent has yet been established to have neuroprotective effects in either disease, advances in our understanding of the aetiopathogenetic basis of cell

Search strategy and selection criteria

References for this Series paper were identified through searches of PubMed from July, 2005 to July, 2013, with the search terms “Parkinson's disease”, “Huntington's disease”, “neuroprotection”, “disease modification”, “aetiology”, “pathogenesis”, “mitochondria”, “α-synuclein”, “huntingtin”, “autophagy”, “mitophagy”, and “prion”. Articles were also identified through searches of the authors' own files. We review only papers published in English. The reference list was based on originality,

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