Despite the putative role of О±-synuclein in LBD, many questions remain, including why it aggregates, how (if at all) it induces neuronal dysfunction and degeneration, and thus its suitability as a target for candidate therapeutics. 2017), suggest an important role for О±-synuclein in pathological processes in LBD. 1997), and downregulation of О±-synuclein levels reducing risk of developing idiopathic PD (Mittal et al. 1997), the presence of О±-synuclein in Lewy bodies (Spillantini et al.

Nevertheless, the observations that mutations in the О±-synuclein gene SNCA cause familial PD (Polymeropoulos et al. The direct pathogenic relevance of Lewy bodies to the neuronal dysfunction and degeneration that characterises LBD is not known (Outeiro et al. In addition to the presence of Lewy bodies, LBD cases are also characterised by nigral depigmentation and striatonigral dopaminergic denervation that is thought to underlie the extrapyramidal features that characterise clinical parkinsonism (Jellinger 2012). The characteristic pathological feature of LBD is intraneuronal inclusions of the protein О±-synuclein termed Lewy bodies (McKeith et al. PD and PDD present with motor symptoms such as rest tremor, bradykinesia, and unsteady gait that can progress into cognitive impairment, whilst DLB typically present with cognitive features that often develop into parkinsonian features similar to PD (McKeith et al. The Lewy body diseases (LBD) include ParkinsonвЂ™s disease (PD), ParkinsonвЂ™s disease dementia (PDD), and dementia with Lewy bodies (DLB), all of which lie on a clinical spectrum of motor and cognitive symptoms (Jellinger and Korczyn 2018). In particular, we will focus on how understanding disease mechanisms in neurometabolic disorders with dysregulated О±-synuclein may generate insights into predisposing factors for О±-synuclein aggregation in idiopathic Lewy body diseases.

In this review, we describe several neurometabolic diseases linked to Lewy body disease mechanisms, and discuss the wider context to pathological overlaps between neurometabolic and Lewy body diseases. Despite these rare diseases occurring in early life, they share many important pathological overlaps with age-associated Lewy body disease, particularly dysregulation of О±-synuclein. However, it is less well known that he also contributed important insights into the neuropathological features of several paediatric neurometabolic diseases, including AlpersвЂ“Huttenlocher syndrome, a syndrome of mitochondrial disease caused by POLG mutations, and infantile neuroaxonal dystrophy, a phenotype resulting from PLA2G6 mutations. Professor Kurt Jellinger is well known for his seminal work on the neuropathology of age-associated neurodegenerative disorders, particularly Lewy body diseases.

Formation allplan 2020