Neuroprotection for Huntington’s Disease: Ready, Set, Slow

Abstract

Summary:The ultimate goal for Huntington's disease (HD) therapeutics is to develop disease-modifying neuroprotective therapies that can delay or prevent illness in those who are at genetic risk and can slow progression in those who are affected clinically. Neuroprotection is the preservation of neuronal structure, function, and viability, and neuroprotective therapy is thus targeted at the underlying pathology of HD, rather than at its specific symptoms. Preclinical target discovery research in HD is identifying numerous distinct targets, along with options for modulating them, with some proceeding into large-scale efficacy studies in early symptomatic HD subjects. The first pilot studies of neuroprotective compounds in premanifest HD are also soon to begin. This review discusses the opportunities for neuroprotection in HD, clinical methodology in premanifest and manifest HD, the clinical assessment of neuroprotection, molecular targets and therapeutic leads, and the current state of clinical development.

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

“…toxic mRNA in HD etiology has also been suggested [7]. HD inheritance is autosomal dominant and consequently the prevailing view is that mHtt mediated symptoms result from a toxic gain-offunction mechanism although loss-of-function mechanisms for mHtt and Htt are also proposed [8,9]. Htt is conserved among vertebrates [10], is localized mainly in cytoplasm and exhibits anti-apopptotic properties [11,12].…”

“…Presently available data indicate at the following mechanisms of mHtt toxicity: protein aggregation, excitotoxicity, oxidative stress, impairment of proteolysis and proteasome, enhanced apoptosis and autophagy, transcription regulation, including epigenetic mechanisms and mitochondria dysfunction [6,8,9,[18][19][20]. Although the functional relationship of Htt to mitochondria is still uncertain [21], it is becoming increasingly apparent that mHtt can impair mitochondrial function directly [22].…”

“…Its domain model does not indicate any particular functions aside from domains that might mediate protein interactions. Indeed, numerous reports indicate that Htt interacts with above 200 proteins which represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, gene expression regulation and metabolism [8,[15][16][17].Presently available data indicate at the following mechanisms of mHtt toxicity: protein aggregation, excitotoxicity, oxidative stress, impairment of proteolysis and proteasome, enhanced apoptosis and autophagy, transcription regulation, including epigenetic mechanisms and mitochondria dysfunction [6,8,9,[18][19][20]. Although the functional relationship of Htt to mitochondria is still uncertain [21], it is becoming increasingly apparent that mHtt can impair mitochondrial function directly [22].…”

Evaluating imaging biomarkers for neurodegeneration in pre-symptomatic Huntington's disease using machine learning techniques

“…For patients with these diseases it is imperative to develop in-vivo measures (biomarkers) that can track early disease-induced neural changes, especially before overt symptoms arise. Such biomarkers could provide metrics to evaluate neural change over time as well as the outcome of neuroprotective trials (reviewed by Bohanna et al, 2008;Hersch and Rosas, 2008).…”

HTRF analysis of soluble huntingtin in PHAROS PBMCs

“…1 mtHtt misfolds, undergoes posttranslational modifications, fragments, and forms soluble oligomers and insoluble intracellular aggregates, [2][3][4] which are differentially toxic. 5,6 Huntingtin (Htt) is the most salient target for neuroprotective therapies [7][8][9] and it is both essential and challenging to reliably measure it 1,2,10 to enable the development of therapies. We adapted a semiquantitative cell-based immunoassay that measures soluble mtHtt and total Htt (tHtt) using homogeneous time-resolved fluorescence (HTRF) Förster resonance energy transfer.…”