Neuroprotective therapy for Huntington’s disease: new prospects and challenges

Abstract

Extraordinary advances in understanding of the molecular bases of neurodegeneration have occurred since the Huntington's disease genetic mutation was discovered. Many relevant routes to neuronal demise in Huntington's disease have been identified including: glutamatergic stress, metabolic insufficiency, oxidative stress, proapoptotic signaling, inflammatory signaling, altered proteolysis, protein aggregation, transcriptional dysregulation, abnormal protein folding and neurotrophin insufficiency. Each represents specific therapeutic opportunities, which are being tested in high-throughput screens as well as in genetic models of Huntington's disease, transgenic mouse models and human clinical trials. Challenges include the uncertain power of these preclinical studies to predict therapeutic efficacy in humans, prioritizing the many approaches for human clinical trials and learning how to perform neuroprotective trials in presymptomatic individuals while protecting them from unwanted genetic information.

Motor timing variability increases in preclinical Huntington's disease patients as estimated onset of motor symptoms approaches

“…This study contributes additional evidence that PFT variability can be a sensitive gauge of impaired basal ganglia function. If this connection were to be established, PFT variability could serve as a reliable preclinical marker for determining the optimal time for initiating neuroprotective treatment meant to forestall or prevent clinical HD onset (Hersch & Rosas, 2001) and for measuring therapeutic efficacy in the context of a clinical trial (Paulsen et al, 2006). Our results also provide support for the view that timing behaviors are more generally disrupted in pre-HD participants.…”

Neuroinflammation in Huntington’s Disease: New Insights with 11C-PBR28 PET/MRI

“…These events ultimately lead to increasingly fragile, atrophic, dysfunctional neurons susceptible to a variety of stressors such as oxidative injury, excitotoxic stress, disordered neurophysiology, proapoptotic signals, malfunctioning proteolysis, and energy depletion, all of which might play roles in neuronal death. 6 Neuroinflammation has been suggested as an important early pathological process in Huntington's disease. It is mediated through the activation of glia and results in the formation of soluble pro-inflammatory molecules, such as cytokines, prostaglandins, and nitric oxide, following activation of nitric oxide synthase, thereby creating response cascades that can negatively impact brain structure and function.…”

“…Proteolysis of mutant htt, whereby abnormal and toxic N-terminal fragments of htt are released, plays a central role in the pathogenesis of this disease. − These toxic htt fragments set in motion a complicated cascade of both damaging and compensatory molecular processes and genetic programs, including neuroinflammation. These events ultimately lead to increasingly fragile, atrophic, dysfunctional neurons susceptible to a variety of stressors such as oxidative injury, excitotoxic stress, disordered neurophysiology, proapoptotic signals, malfunctioning proteolysis, and energy depletion, all of which might play roles in neuronal death …”

Sustained complete response and low complication rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis

“…1 H‐MRS has the potential of defining early onset neurochemical changes and of monitoring response to treatment 15. Such information is critical in JHD where degeneration can be devastating in a developing child.…”