Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. and neuronal loss accompanied by micro- and astrogliosis are further distinctive features of MSA-related neuropathology present in numerous brain regions. Besides summarizing current symptomatic treatment strategies in MSA, this review critically reflects upon potential cellular targets and disease-modifying approaches for MSA such as (I) targeting -syn pathology, (II) intervening neuroinflammation, and (III) neuronal loss. Although these single compound trials are aiming to interfere with distinct pathogenetic steps in MSA, a combined approach may be necessary to slow down the rapid progression of the oligodendroglial associated synucleinopathy. gene and physiologically involved in neurotransmitter synthesis and release [5]. However, its accumulation is closely associated with a variety of neurodegenerative diseases, classified as -synucleinopathies. While the intracellular expression of -syn is well described for neurons, the origin of oligodendroglial GCIs is still debated. One finding suggests an endogenous expression of -syn in oligodendrocytes, strengthened by the identification of -syn transcripts in isolated nuclei of oligodendroglial lineage cells derived from rodents and humans [6]. CP-673451 novel inhibtior Alternatively, an uptake of -syn from neighboring cells CP-673451 novel inhibtior or the extracellular environment combined with the involvement of specific oligodendroglial proteins e.g., tubulin polymerization-promoting protein (TPPP/p25) have been proposed [7,8,9,10]. Even though the origin of -syn in MSA has not yet been clarified, its accumulation may interfere with important oligodendroglial functions. Despite an unaltered number of oligodendrocytes in white matter regions in the fore- and hindbrain, myelin formation is severely impaired resulting in severe myelin loss [11,12,13,14,15,16,17,18]. Reduced myelination is accompanied by pronounced neuronal loss in distinct brain regions, including the motor cortex, dorsolateral putamen, globus pallidus, cerebellum, and substantia nigra correlating with GCI density and disease progression [3,13,15,19]. Furthermore, neuroinflammation is an important pathological feature of MSA consisting of micro- and astrogliosis driving an increased release of inflammatory cytokines such as tumor necrosis factor alpha (TNF), interferons, and interleukins (IL), predominantly in the white matter of CP-673451 novel inhibtior the central nervous system (CNS) [20,21,22,23]. Although considered as a sporadic disease, several familial cases of MSA were observed suggesting a genetic predisposition for the disease. Indeed, mutations in the gene, encoding the enzyme para-hydroxybenzoate-polyprenyl transferase have been identified in a Japanese MSA patient cohort Rabbit polyclonal to AFF2 and were proposed as a genetic risk factor [24]. Located at the inner mitochondrial membrane, coenzyme Q10 is an essential cofactor for the mitochondrial respiratory chain. Thus, mutations in the gene may result in mitochondrial CP-673451 novel inhibtior dysfunction, a crucial pathogenic event frequently associated with neurodegenerative diseases [25]. However, conflicting results have emerged since mutations in the gene were not detected in non-Asian patient cohorts [24,26]. Further genetic studies linked specific SNCA polymorphisms [27,28,29] and -syn mutations such as A53E and G51D with an increased risk of developing MSA [30,31]. Besides a genetic predisposition, several environmental factors including the exposure to metal dusts and fumes, plastic monomers, and pesticides have been discussed as potential risk factors. However, how and to which extent these factors contribute to MSA pathology needs further investigation [32,33]. So far, aging CP-673451 novel inhibtior remains the sole, well-accepted risk factor for developing MSA. Due to the limited knowledge regarding the precise underlying pathogenesis and molecular targets triggering MSA, there is currently no disease-modifying therapy available for MSA patients. However, the rapid and severe disease progression as well as the orphan disease status makes MSA particularly interesting for advanced drug development and accelerated approval. This review provides an overview of the neuropathology of MSA, summarizes current symptomatic treatment strategies, and more importantly reflects on potential disease-modifying approaches for MSA. 2. Neuropathology of MSA Neuropathological prerequisite of certain MSA are proteinaceous aggregates mainly recognized in the cytoplasm of oligodendrocytes visualized by Gallyas metallic staining. GCIs or so-called PappCLantos body are agryophilic, granulated, and loosely packed with a diameter of 5C20 m. They appear in numerous morphologies having half-moon, triangular, or oval shape [3]. Less regularly, additional inclusions have been found in MSA individuals including protein aggregates in the nuclei of oligodendrocytes and neurons, in.