Are many of the common neurodegenerative conditions driven in their onset and progression by the consequences of persistent viral infection? The evidence is compelling, but not completely convincing at the present time. Given that these conditions are likely the result of a number of quite different, interacting mechanisms, including viral infection, vascular aging, immune system aging, mitochondrial dysfunction, and aggregation of toxic proteins, amongst others, it is a challenge to produce cut and dried data to show, definitively, the degree to which any one cause contributes. In the case of viral infection, there are studies suggesting yes, and there are studies suggesting no - the usual situation for a complex system in which more work will be needed to better understand what is going on under the hood.
Neurodegenerative diseases (NDs) are fatal chronic diseases of the central nervous system (CNS), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and transmissible spongiform encephalopathies (TSEs). A hallmark of NDs is the intracellular or extracellular deposition of cellular proteins into ordered high-molecular weight fibrils, termed amyloid. Amyloid fibrils then act as seeds that bind and convert proteins of the same kind into their abnormal isoforms (seeding). Protein aggregation occurs sequentially in anatomically connected areas, suggesting a progressive spreading throughout the CNS of affected individuals. Approximately 90% of NDs occur sporadically, and only few cases are linked to mutations in aggregation-prone proteins or proteins involved in their processing or trafficking. The etiology of idiopathic NDs remains unknown.
NDs are multifactorial diseases, triggered by enhanced age as well as genetic and environmental risk factors. Pathogens, and especially viruses, are suspected to act as etiological factors in several NDs. An impressive number of studies highlights that viruses, through their capacity to hijack the host cell machinery and induce inflammation, trigger and/or contribute to degenerative processes. Viral infections can activate astrocytes and microglia or induce CNS infiltration by peripheral immune cells, thereby causing neuroinflammation. Some viruses can enter the CNS and affect neurodegeneration via lytic egress from infected neurons by impairing neuronal processes or by inducing neuronal apoptosis. In this review, we discuss how viruses can also directly contribute to disease-associated protein misfolding and subsequent processes of protein aggregate spreading.