The role of neurotrophins in muscle under physiological and pathological conditions

This review summarizes the various effects of neurotrophins in skeletal muscle and how these proteins act as potential regulators of development, maintenance, function, and regeneration of skeletal muscle fibers. Increasing evidence suggests that this family of neurotrophic factors not only modulates survival and function of innervating motoneurons and proprioceptive neurons but also development and differentiation of myoblasts and muscle fibers. Neurotrophins and neurotrophin receptors play a role in the coordination of muscle innervation and functional differentiation of neuromuscular junctions. However, neurotrophin receptors are also expressed in differentiating muscle cells, in particular at early developmental stages in myoblasts before they fuse. In adults with pathological conditions such as human degenerative and inflammatory muscle disorders, variations of neurotrophin expression are found, but the role of neurotrophins under such conditions is still not clear. The goal of this review is to provide a basis for a better understanding and future studies on the role of these factors under such pathological conditions and for treatment of human muscle diseases.     

Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters

Accumulation of alpha-synuclein has been associated with neurodegenerative disorders, such as Lewy body disease and multiple system atrophy. We previously showed that expression of wild-type human alpha-synuclein in transgenic mice results in motor and dopaminergic deficits associated with inclusion formation. To determine whether different levels of human alpha-synuclein expression from distinct promoters might result in neuropathology mimicking other synucleopathies, we compared patterns of human alpha-synuclein accumulation in the brains of transgenic mice expressing this molecule from the murine Thy-1 and platelet-derived growth factor (PDGF) promoters. In murine Thy-1-human alpha-synuclein transgenic mice, this protein accumulated in synapses and neurons throughout the brain, including the thalamus, basal ganglia, substantia nigra, and brainstem. Expression of human alpha-synuclein from the PDGF promoter resulted in accumulation in synapses of the neocortex, limbic system, and olfactory regions as well as formation of inclusion bodies in neurons in deeper layers of the neocortex. Furthermore, one of the intermediate expressor lines (line M) displayed human alpha-synuclein expression in glial cells mimicking some features of multiple system atrophy. These results show a more widespread accumulation of human alpha-synuclein in transgenic mouse brains. Taken together, these studies support the contention that human alpha-synuclein expression in transgenic mice might mimic some neuropathological alterations observed in Lewy body disease and other synucleopathies, such as multiple system atrophy.     

Molecular regulation of dendritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases

The structure and dynamics of dendritic spines reflect the strength of synapses, which are severely affected in different brain diseases. Therefore, understanding the ultra-structure, molecular signaling mechanism(s) regulating dendritic spine dynamics is crucial. Although, since last century, dynamics of spine have been explored by several investigators in different neurological diseases, but despite countless efforts, a comprehensive understanding of the fundamental etiology and molecular signaling pathways involved in spine pathology is lacking. The purpose of this review is to provide a contextual framework of our current understanding of the molecular mechanisms of dendritic spine signaling, as well as their potential impact on different neurodegenerative and psychiatric diseases, as a format for highlighting some commonalities in function, as well as providing a format for new insights and perspectives into this critical area of research. Additionally, the potential strategies to restore spine structure–function in different diseases are also pointed out. Overall, these informations should help researchers to design new drugs to restore the structure–function of dendritic spine, a “hot site” of synaptic plasticity.