Therapeutic approaches to preventing cell death in Huntington disease
Highlights
► Huntington disease is one of numerous neurodegenerative disorders. ► Inhibiting neuronal cell death is one strategy to combat Huntington disease. ► Inhibiting cell-death proteins or activating autophagy leads to neuroprotection. ► Numerous proteins are not amenable to classical methods of drug discovery. ► Fragment-based drug discovery is an alternative method to identify potent drugs.
Introduction
Neurodegenerative diseases encompass a large class of disorders that affect millions of individuals around the world. Broadly, such diseases can be defined as those that selectively and progressively induce neuronal death or dysfunction, especially in midlife. Currently, there are few effective therapies for such disorders. The number of patients affected by neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and HD, is estimated to increase over time due, to the growing size of the elderly population (Hebert et al., 2001, Thrall, 2005). The cost of care in the US for AD patients alone surpasses $100 billion (Alzheimer's Association, 2010). Delaying the onset or slowing the development of neurodegeneration would have a significant benefit: it would decrease the economic burden and improve the quality of life of affected individuals and their families (Alzheimer's Association, 2010, Thrall, 2005).
Here, we focus on one neurological disorder, HD, and emerging drug discovery approaches involving fragment-based and computational drug design that can be applied to developing small molecule inhibitors of proteins that induce cell-death. We begin by reviewing what is known about HD (Section 2) and then examine the pro-cell-death targets that may be of therapeutic benefit to HD (Section 3). In the final section, we describe FBDD and how it may be used in drug discovery efforts for HD and other neurodegenerative diseases (Section 4).
Section snippets
Huntington disease
There have been several extensive reviews published on HD (Imarisio et al., 2008, Ross and Tabrizi, 2011, Walker, 2007, Zuccato et al., 2010). Here, we provide only a brief overview of the disease.
Regulated cell death pathways and HD targets
Classical programmed cell death was initially used to describe apoptosis, a tightly regulated, active, self-terminating process that Kerr morphologically characterized in 1972 to contrast with accidental cell death (Kerr et al., 1972). Today, there are numerous cell death pathways that have been identified. In addition to the well-established regulated cell death pathway of apoptosis, novel pathways and processes involving cell death are being identified, such as ferroptosis (Dixon et al., 2012
Drug design
Identifying potential therapeutic targets in HD is only the first stage of creating new therapies. The next challenge is designing inhibitors for those targets. Since the first introduction of Pfizer's “high-throughput screen” in 1948 (Janzen, 2002), the high-throughput screening (HTS) approach for lead elicitation has become ubiquitous within the pharmaceutical industry (Fischer and Hubbard, 2009, Janzen, 2002) and academia. However, limitations of this method have started to emerge and a
Conclusions
Developing pharmaceutical agents to counteract neurodegenerative diseases has always posed a grand challenge. Primarily, our understanding of the molecular pathways involved in these diseases is still limited. Furthermore, the proteins that are known to be involved in neurodegenerative disorders are not easy targets to modulate with traditional approaches. To overcome the first problem, research has focused on the most downstream effectors of neurodegeneration—cell death pathways. There is an
Acknowledgments
We would like to thank R.R. Letso and B.E. Kaplan for their thorough review of the manuscript. We apologize to investigators whose work we did not include in this review due to time and space restrictions. BRS is an Early Career Scientist of the Howard Hughes Medical Institute, and is supported by additional funding from the Arnold and Mabel Beckman Foundation, NYSTAR and the National Institutes of Health (R01CA097061, R01GM085081 and R01CA161061). AK is supported by the Training Program in
References (276)
- et al.
Symptomatic treatment of Huntington disease
Neurotherapeutics
(2008) - et al.
Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta
Neuron
(2008) - et al.
Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington's disease
Brain Research Bulletin
(2002) - et al.
A cell-based screen for drugs to treat Huntington's disease
Neurobiology of Disease
(2004) - et al.
Identification of potent and novel small-molecule inhibitors of caspase-3
Bioorganic & Medicinal Chemistry Letters
(2003) - et al.
Human ICE/CED-3 protease nomenclature
Cell
(1996) Huntingtin aggregation and toxicity in Huntington's disease
Lancet
(2003)- et al.
Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death
Cell
(1996) - et al.
The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington's disease
Current Biology
(2011) - et al.
Fragment-based lead discovery: leads by design
Drug Discovery Today
(2005)
Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene/allele-specific silencing of mutant huntingtin
Molecular Therapy
Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease
Neurobiology of Disease
Huntingtin-interacting protein 1-mediated neuronal cell death occurs through intrinsic apoptotic pathways and mitochondrial alterations
FEBS Letters
Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration
Cell
Flanking polyproline sequences inhibit beta-sheet structure in polyglutamine segments by inducing PPII-like helix structure
Journal of Molecular Biology
Pridopidine for the treatment of motor function in patients with Huntington's disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial
The Lancet Neurology
Ferroptosis: an iron-dependent form of non-apoptotic cell death
Cell
Initial experience in the treatment of inherited mitochondrial disease with EPI-743
Molecular Genetics and Metabolism
Fragment-based lead discovery: a chemical update
Current Opinion in Biotechnology
Glutamate toxicity in the striatum of the R6/2 Huntington's disease transgenic mice is age-dependent and correlates with decreased levels of glutamate transporters
Neurobiology of Disease
Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules
Cell
Potential of cystamine and cysteamine in the treatment of neurodegenerative diseases
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntington's Disease
Pharmacological Research
Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin
Cell
The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs
Cell
Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain
Journal of Biological Chemistry
Fragment-based drug discovery: what has it achieved so far?
Current Topics in Medicinal Chemistry
Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat
Somatic Cell and Molecular Genetics
HEAT repeats in the Huntington's disease protein
Nature Genetics
Weight loss in Huntington disease increases with higher CAG repeat number
Neurology
Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation
Brain
NMDA receptors: recent insights and clinical correlations
Neurology
Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin
Molecular Biology of the Cell
Effectiveness of physiotherapy, occupational therapy, and speech pathology for people with Huntington's disease: a systematic review
Neurorehabilitation & Neural Repair.
970 million druglike small molecules for virtual screening in the chemical universe database GDB-13
Journal of American Chemical Society
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma
Nature
Pharmacological management of Huntington's disease: an evidence-based review
Current Pharmaceutical Design
Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase
Journal of Clinical Investigation
Structural definition of the F-actin-binding THATCH domain from HIP1R
Nature Structural & Molecular Biology
Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates
Proceedings of the National Academy of Sciences United States of America
Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia
Annals of Neurology
Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease
Nature Medicine
Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release
Human Molecular Genetics
Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design
Journal of Medicinal Chemistry
Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6
Journal of Medicinal Chemistry
Structure of importin-beta bound to the IBB domain of importin-alpha
Nature
Cited by (20)
An enquiry to the role of CB1 receptors in neurodegeneration
2023, Neurobiology of DiseaseRegulatory roles of the miR-200 family in neurodegenerative diseases
2019, Biomedicine and PharmacotherapyCitation Excerpt :Neurodegenerative diseases are progressive and result in severe disability and shortened life expectancy, so effective treatments that slow or stop disease progression are extremely needed [12]. Unfortunately, at present, managements of these diseases are limited to a few treatment options in the early stage, and these treatment strategies only control some symptoms (e.g. movement disorders, psychiatric problems), but the courses of diseases cannot be modified [13]. The reason is partly that the underlying mechanisms of many neurodegenerative diseases remain still unknown.
Designing aptamers which respond to intracellular oxidative stress and inhibit aggregation of mutant huntingtin
2018, Free Radical Biology and MedicineCitation Excerpt :The stress-inducible aptamers were successful in reducing aggregation of 103Q-htt and consequently cytotoxicity (Fig. 3B). Aggregation of mutant huntingtin causes death of striatal neurons [18,19]. In cells expressing 103Q-htt with oxidative stress-inducible aptamers, viability was significantly higher as compared to the empty vector or non-inhibitor(s) (Fig. 3C).
Olive Oil and Huntington's Disease
2015, Diet and Nutrition in Dementia and Cognitive DeclineThe Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) C terminus plays a key role in protein stability, but its farnesylation is not required for membrane association in primary neurons
2014, Journal of Biological ChemistryCitation Excerpt :It has been proposed that UCH-L1 possesses E4 ubiquitin ligase activity, which promotes polyubiquitination of α-synuclein to pathologically alter basal turnover (8). Furthermore, it has been proposed that this interaction is mediated specifically by farnesylated UCH-L1M (9), and, on the basis of this finding, small molecule farnesyltransferase inhibitor drugs such as LNK-754 are currently in clinical trials to inhibit or reduce the levels of farnesylated UCH-L1M (29, 30). Although our study does not preclude potential roles for FTIs in treating neurodegeneration, our data strongly suggest that they do not act by decreasing the membrane association of UCH-L1M.
Towards small molecules as therapies for alzheimer's disease and other neurodegenerative disorders
2014, Drug Design and Discovery in Alzheimer's Disease