Vapb/Amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response.

Missense mutations (P56S) in Vapb are associated with autosomal dominant motor neuron diseases: amyotrophic lateral sclerosis and lower motor neuron disease. Although transgenic mice overexpressing the mutant vesicle-associated membrane protein-associated protein B (VAPB) protein with neuron-specific promoters have provided some insight into the toxic properties of the mutant proteins, their role in pathogenesis remains unclear. To identify pathological defects in animals expressing the P56S mutant VAPB protein at physiological levels in the appropriate tissues, we have generated Vapb knock-in mice replacing wild-type Vapb gene with P56S mutant Vapb gene and analyzed the resulting pathological phenotypes. Heterozygous P56S Vapb knock-in mice show mild age-dependent defects in motor behaviors as characteristic features of the disease. The homozygous P56S Vapb knock-in mice show more severe defects compared with heterozygous mice reflecting the dominant and dose-dependent effects of P56S mutation. Significantly, the knock-in mice demonstrate accumulation of P56S VAPB protein and ubiquitinated proteins in cytoplasmic inclusions, selectively in motor neurons. The mutant mice demonstrate induction of ER stress and autophagic response in motor neurons before obvious onset of behavioral defects, suggesting that these cellular biological defects might contribute to the initiation of the disease. The P56S Vapb knock-in mice could be a valuable tool to gain a better understanding of the mechanisms by which the disease arises.

Pharmacological Inhibition of Brain EGFR Activation By a BBB-penetrating Inhibitor, AZD3759, Attenuates α-synuclein Pathology in a Mouse Model of α-Synuclein Propagation.

Aggregation and deposition of α-synuclein (α-syn) in Lewy bodies within dopamine neurons of substantia nigra (SN) is the pathological hallmark of Parkinson's disease (PD). These toxic α-syn aggregates are believed to propagate from neuron-to-neuron and spread the α-syn pathology throughout the brain beyond dopamine neurons in a prion-like manner. Targeting propagation of such α-syn aggregates is of high interest but requires identifying pathways involving in this process. Evidence from previous Alzheimer's disease reports suggests that EGFR may be involved in the prion-like propagation and seeding of amyloid-ß. We show here that EGFR regulates the uptake of exogenous α-syn-PFFs and the levels of endogenous α-syn in cell cultures and a mouse model of α-syn propagation, respectively. Thus, we tested the therapeutic potentials of AZD3759, a highly selective BBB-penetrating EGFR inhibitor, in a preclinical mouse model of α-syn propagation. AZD3759 decreases activated EGFR levels in the brain and reduces phosphorylated α-synuclein (pSyn) pathology in brain sections, including striatum and SN. As AZD3759 is already in the clinic, this paper's results suggest a possible repositioning of AZD3759 as a disease-modifying approach for PD.

One Step Into the Future: New iPSC Tools to Advance Research in Parkinson's Disease and Neurological Disorders.

Studying Parkinson's disease (PD) in the laboratory presents many challenges, the main one being the limited availability of human cells and tissue from affected individuals. As PD is characterized by a loss of dopaminergic (DA) neurons in the brain, it is nearly impossible for researchers to access and extract these cells from living patients. Thus, in the past PD research has focused on the use of patients' post-mortem tissues, animal models, or immortalized cell lines to dissect cellular pathways of interest. While these strategies deepened our knowledge of pathological mechanisms in PD, they failed to faithfully capture key mechanisms at play in the human brain. The emergence of induced pluripotent stem cell (iPSC) technology is revolutionizing PD research, as it allows for the differentiation and growth of human DA neurons in vitro, holding immense potential not only for modelling PD, but also for identifying novel therapies. However, to reproduce the complexity of the brain's environment, researchers are recognizing the need to further develop and refine iPSC-based tools. In this review, we provide an overview of different systems now available for the study of PD, with a particular emphasis on the potential and limitations of iPSC as research tools to generate more relevant models of PD pathophysiology and advance the drug discovery process.