Abstract
Parkinson’s disease (PD) is a neurodegenerative disease linked with the loss of dopaminergic neurons in the brain region called substantia nigra and caused by unknown pathogenic mechanisms. Two currently recognized prominent features of PD are an inflammatory response manifested by glial reaction and T-cell infiltration, as well as the presence of various toxic mediators derived from activated glial cells. PD or parkinsonism has been described after infection with several different viruses and it has therefore been hypothesized that a viral infection might play a role in the pathogenesis of the disease. We investigated formalin-fixed post-mortem brain tissue from 9 patients with Parkinson’s disease and 11 controls for the presence of Ljungan virus (LV) antigen using a polyclonal antibody against the capsid protein of this recently identified picornavirus with neurotropic properties, suspected of being both a human and an animal pathogen. Evidence of viral antigen was found in 7 out of 9 Parkinson’s disease cases and in only 1 out of 11 controls (p = 0.005). The picornavirus antigen was present in dopamine-containing neurons of the substantia nigra. We propose that LV or an LV-related virus initiates the pathological process underlying sporadic PD. LV-related picornavirus antigen has also been reported in patients with Alzheimer’s disease. Potentially successful antiviral treatment in Alzheimer’s disease suggests a similar treatment for Parkinson's disease. Amantadine, originally developed as an antiviral drug against influenza infection, has also been used for symptomatic treatment of patients with PD for more than 50 years and is still commonly used by neurologists today. The fact that amantadine also has an antiviral effect on picornaviruses opens the question of this drug being re-evaluated as potential PD therapy in combination with other antiviral compounds directed against picornaviruses.
Highlights
Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal lobe degeneration (FTLD) and Alzheimer’s disease (AD) are all characterized by progressive degeneration and the loss of specific subsets of neurons, leading to decline in brain functions such as cognition and locomotor control [1]
The finding that Ljungan virus (LV) was related to the rodent-borne picornavirus, encephalomyocarditis virus (EMCV), prompted us to expand our search effort to include all diseases in the repertoire of this virus
We investigated antiviral compounds alone and in combination focusing on drugs with reported effect on picornaviruses and that have already been approved for human use
Summary
Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal lobe degeneration (FTLD) and Alzheimer’s disease (AD) are all characterized by progressive degeneration and the loss of specific subsets of neurons, leading to decline in brain functions such as cognition and locomotor control [1]. Neurodegenerative diseases have distinct clinical manifestations depending on the localization of brain pathology, and share many features such as protein aggregation and the formation of inclusion bodies [2]. A growing body of epidemiological and experimental data points to the fact that chronic viral infections may cause neurodegenerative diseases [5]. In the case of PD, various genetic and environmental factors have been associated with the disease and the number of known genetic risk factors has increased dramatically [6]. These known loci presently account for only approximately 20% of PD risk, meaning that a substantial proportion of PD remains unexplained on the bases of currently known genetic associations [6]
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