The etiology of Parkinson's disease (PD) is complex and most likely involves numerous environmental and heritable risk factors. Recent studies establish that central and peripheral inflammation occurs in the prodromal stage of the disease and sustains disease progression. Aging, heritable risk factors, or environmental exposures may contribute to the initiation of central or peripheral inflammation. One emerging hypothesis is that inflammation plays a critical role in PD neuropathology. Increasing evidence suggest that activation of the peripheral immune system exacerbates the discordant central inflammatory response and synergistically drives neurodegeneration. We provide an overview of current knowledge on the temporal profile of central and peripheral immune responses in PD and discuss the potential synergistic effects of the central and peripheral inflammation in disease development. The understanding of the nature of the chronic inflammation in disease progression and the possible risk factors that contribute to altered central and peripheral immune responses will offer mechanistic insights into PD etiology and pathology and benefit the development of effective tailored therapeutics for human PD.

Parkinson's disease (PD) is a chronic and progressive disorder characterized neuropathologically by loss of dopamine neurons in the substantia nigra, intracellular proteinaceous inclusions, reduction of dopaminergic terminals in the striatum, and increased neuroinflammatory cells. The consequent reduction of dopamine in the basal ganglia results in the classical parkinsonian motor phenotype. A growing body of evidence suggest that neuroinflammation mediated by microglia, the resident macrophage-like immune cells in the brain, play a contributory role in PD pathogenesis. Microglia participate in both physiological and pathological conditions. In the former, microglia restore the integrity of the central nervous system and, in the latter, they promote disease progression. Microglia acquire different activation states to modulate these cellular functions. Upon activation to the M1 phenotype, microglia elaborate pro-inflammatory cytokines and neurotoxic molecules promoting inflammation and cytotoxic responses. In contrast, when adopting the M2 phenotype microglia secrete anti-inflammatory gene products and trophic factors that promote repair, regeneration, and restore homeostasis. Relatively little is known about the different microglial activation states in PD and a better understanding is essential for developing putative neuroprotective agents. Targeting microglial activation states by suppressing their deleterious pro-inflammatory neurotoxicity and/or simultaneously enhancing their beneficial anti-inflammatory protective functions appear as a valid therapeutic approach for PD treatment. In this review, we summarize microglial functions and, their dual neurotoxic and neuroprotective role in PD. We also review molecules that modulate microglial activation states as a therapeutic option for PD treatment.

Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). In the past decade, single-chain fragment variable (scFv) -based immunotherapies have been developed to target abnormal proteins or various forms of protein aggregates including Aβ, SNCA, Htt, and PrP proteins. The scFvs are produced by fusing the variable regions of the antibody heavy and light chains, creating a much smaller protein with unaltered specificity. Because of its small size and relative ease of production, scFvs are promising diagnostic and therapeutic reagents for protein misfolded diseases. Studies have demonstrated the efficacy and safety of scFvs in preventing amyloid protein aggregation in preclinical models. Herein, we discuss recent developments of these immunotherapeutics. We review efforts of our group and others using scFv in neurodegenerative disease models. We illustrate the advantages of scFvs, including engineering to enhance misfolded conformer specificity and subcellular targeting to optimize therapeutic action.

The pharmaceutical industry's development of therapeutic medications for the treatment of Parkinson's disease (PD) endures, as a result of the continuing need for better agents, and the increased clinical demand due to the aging population. Each new drug offers advantages and disadvantages to patients when compared to other medical offerings or surgical options. Deep brain stimulation (DBS) has become a standard surgical remedy for the effective treatment of select patients with PD, for whom most drug regimens have failed or become refractory. Similar to DBS as a surgical option, gene therapy for the treatment of PD is evolving as a future option. In the four different PD gene therapy approaches that have reached clinical trials investigators have documented an excellent safety profile associated with the stereotactic delivery, viral vectors and doses utilized, and transgenes expressed. In this article, we review the clinically relevant gene therapy strategies for the treatment of PD, concentrating on the published preclinical and clinical results, and the likely mechanisms involved. Based on these presentations, we advance an analysis of how the nature of the gene therapy used may eventually expand the scope and utility for the management of PD.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Objective

Certain Big 5 personality dimensions have been repeatedly linked to global measures of cognitive function and outcome categories. We examined whether the Big 5 or their specific components showed differential evidence of associations with specific neurocognitive domains.

Methods

Participants were 179 older adults (70+) from a broader study on cognitive aging. The NEO-Five Factor Inventory and a comprehensive battery of neuropsychological tests were used.

Results

Adjusted for age, gender, and years of education, probability values, Bayes Factors, and measures effect size from linear models suggested strong evidence for associations between better delayed recall memory and higher Conscientiousness (principally the facets of Goal-Striving and Dependability) and Openness (specifically the Intellectual Interest component). Better executive function and attention showed moderate to strong evidence of associations with lower Neuroticism (especially the Self-conscious Vulnerability facet) and higher Conscientiousness (mostly the Dependability facet). Better language functioning was linked to higher Openness (specifically, the Intellectual Interests facet). Worse visual-spatial function was strongly associated with higher Neuroticism.

Conclusion

Different tests of neurocognitive functioning show varying degrees of evidence for associations with different personality traits. Better understanding of the patterning of neurocognitive-personality linkages may facilitate grasp of underlying mechanisms and/or refine understanding of co-occurring clinical presentation of personality traits and specific cognitive deficits.

Mitochondrial transport is critical for maintenance of normal neuronal function. Here, we identify a novel mitochondria protein, hypoxia up-regulated mitochondrial movement regulator (HUMMR), which is expressed in neurons and is markedly induced by hypoxia-inducible factor 1 alpha (HIF-1alpha). Interestingly, HUMMR interacts with Miro-1 and Miro-2, mitochondrial proteins that are critical for mediating mitochondrial transport. Interestingly, knockdown of HUMMR or HIF-1 function in neurons exposed to hypoxia markedly reduces mitochondrial content in axons. Because mitochondrial transport and distribution are inextricably linked, the impact of reduced HUMMR function on the direction of mitochondrial transport was also explored. Loss of HUMMR function in hypoxia diminished the percentage of motile mitochondria moving in the anterograde direction and enhanced the percentage moving in the retrograde direction. Thus, HUMMR, a novel mitochondrial protein induced by HIF-1 and hypoxia, biases mitochondria transport in the anterograde direction. These findings have broad implications for maintenance of neuronal viability and function during physiological and pathological states.

Preclinical investigators have implicated several microRNAs as regulators of gene expression promoting neural plasticity following experimental stroke in rodent models. Our goal was to determine whether similar microRNAs might be identifiable in plasma of humans with variable recovery from stroke. Plasma was collected 19 days post-stroke from 27 participants with mild-moderate upper extremity impairment enrolled in the Critical Periods After Stroke Study (CPASS). MicroRNA expression was assessed using TaqMan microRNA assays. Good clinical recovery was defined as ≥6 point change in the Action Research Arm Test (ARAT) score from baseline to 6 months, with 22 subjects showing good and 5 showing poor recovery. When comparing the good versus poor recovery groups, six microRNAs showed significantly increased expression - miR-371-3p, miR-524, miR-520g, miR-1255A, miR-453, and miR-583, while 3 showed significantly decreased expression - miR-941, miR-449b, and miR-581. MiR-371-3p and miR-941 have previously been associated with neural repair mechanisms; none of the significant microRNAs have previously been associated with stroke. The 9 microRNAs converge on pathways associated with axonal guidance, developmental biology, and cancer. We conclude that plasma microRNAs may be informative regarding human neural repair mechanisms during stroke recovery and probably differ from those seen in experimental stroke models.

It is known that culture media (CM) promotes cellular growth, adhesion, and protects explanted primary brain cells from in vitro stresses. The fetal bovine serum (FBS) supplement used in most CM, however, contains significant quantities of extracellular vesicles (EVs) that confound quantitative and qualitative analyses from the EVs produced by the cultured cells. We quantitatively tested the ability of common FBS EV-depletion protocols to remove exogenous EVs from FBS-supplemented CM and evaluated the influence such methods have on primary astrocyte culture growth and viability. We assessed two methodologies utilized for FBS EV removal prior to adding to CM: (1) an 18-h ultracentrifugation (UC); and (2) a commercial EV-depleted FBS (Exo-FBS™). Our analysis demonstrated that Exo-FBS™ CM provided the largest depletion (75%) of total FBS EVs, while still providing 6.92 × 10⁸ ± 1.39 × 10⁸ EVs/mL. In addition, both UC and Exo-FBS™ CM resulted in poor primary astrocyte cell growth and viability in culture. The two common FBS EV-depletion methods investigated, therefore, not only contaminate in vitro primary cell-derived EV analyses, but also provide a suboptimal environment for primary astrocyte cell growth and viability. It appears likely that future CM optimization, using a serum-free alternative, might be required to advance analyses of cell-specific EVs isolated in vitro.