Extracellular heat shock proteins in neurodegenerative diseases: New perspectives.

One pathological hallmark of neurodegenerative diseases and CNS trauma is accumulation of insoluble, hydrophobic molecules and protein aggregations found both within and outside cells. These may be the consequences of an inadequate or overburdened cellular response to stresses resulting from potentially toxic changes in extra- and intracellular environments. The upregulated expression of heat shock proteins (HSPs) is one example of a highly conserved cellular response to both internal and external stress. Intracellularly these proteins act as chaperones, playing vital roles in the folding of nascent polypeptides, the translocation of proteins between subcellular locations, and the disaggregation of misfolded or aggregated proteins in an attempt to maintain cellular proteostasis during both homeostatic and stressful conditions. While the predominant study of the HSPs has focused on their intracellular chaperone functions, it remains unclear if all neuronal populations can mount a complete stress response. Alternately, it is now well established that some members of this family of proteins can be secreted by nearby, non-neuronal cells to act in the extracellular environment. This review addresses the current literature detailing the use of exogenous and extracellular HSPs in the treatment of cellular and animal models of neurodegenerative disease. These findings offer a new measure of therapeutic potential to the HSPs, but obstacles must be overcome before they can be efficiently used in a clinical setting.

Inflammation, Immunity, and amyotrophic lateral sclerosis: I. Etiology and pathology.

Amyotrophic lateral sclerosis (ALS) is a severely debilitating disease characterized by progressive degeneration of motor neurons. Charcot first described ALS in 18691 ; however, its pathogenesis remains unknown, and effective treatments remain elusive. It is apparent that new paradigms must be investigated to understand the effectors of ALS, including inflammation, immune responses, and the body's response to stress and injury. Herein we discuss the potential role of the immune system in ALS pathogenesis and critically review evidence from patient and animal studies. Although immune system components may indeed play a role in ALS pathogenesis, studies implicating immune cells, antibodies, and cytokines in early disease pathology are limited. We propose more focused studies that examine the role of the immune system together with characterized pathogenesis to determine when, where, and if immune and inflammatory processes are critical to disease progression, and thus worthy targets of intervention. Muscle Nerve 59:10-22, 2019.

Inflammation, immunity, and amyotrophic lateral sclerosis: II. immune-modulating therapies.

With the emerging popularity of immune-modulatory therapies to treat human diseases there is a need to step back from hypotheses aimed at assessing a condition in a single-system context and instead take into account the disease pathology as a whole. In complex diseases, such as amyotrophic lateral sclerosis (ALS), the use of these therapies to treat patients has been largely unsuccessful and likely premature given our lack of understanding of how the immune system influences disease progression and initiation. In addition, we still have an incomplete understanding of the role of these responses in our model systems and how this may translate clinically to human patients. In this review we discuss preclinical evidence and clinical trial results for a selection of recently conducted studies in ALS. We provide evidence-based reasoning for the failure of these trials and offer suggestions to improve the design of future investigations. Muscle Nerve 59:23-33, 2019.