Exploring the genetics and non-cell autonomous mechanisms underlying ALS/FTLD

Abstract

Although amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, was first described in 1874, a flurry of genetic discoveries in the last 10 years has markedly increased our understanding of this disease. These findings have not only enhanced our knowledge of mechanisms leading to ALS, but also have revealed that ALS shares many genetic causes with another neurodegenerative disease, frontotemporal lobar dementia (FTLD). In this review, we survey how recent genetic studies have bridged our mechanistic understanding of these two related diseases and how the genetics behind ALS and FTLD point to complex disorders, implicating non-neuronal cell types in disease pathophysiology. The involvement of non-neuronal cell types is consistent with a non-cell autonomous component in these diseases. This is further supported by studies that identified a critical role of immune-associated genes within ALS/FTLD and other neurodegenerative disorders. The molecular functions of these genes support an emerging concept that various non-autonomous functions are involved in neurodegeneration. Further insights into such a mechanism(s) will ultimately lead to a better understanding of potential routes of therapeutic intervention. Facts ALS and FTLD are severe neurodegenerative disorders on the same disease spectrum. Multiple cellular processes including dysregulation of RNA homeostasis, imbalance of proteostasis, contribute to ALS/FTLD pathogenesis. Aberrant function in non-neuronal cell types, including microglia, contributes to ALS/FTLD. Strong neuroimmune and neuroinflammatory components are associated with ALS/FTLD patients. Open Questions Why can patients with similar mutations have different disease manifestations, i.e., why do C9ORF72 mutations lead to motor neuron loss in some patients while others exhibit loss of neurons in the frontotemporal lobe? Do ALS causal mutations result in microglial dysfunction and contribute to ALS/FTLD pathology? How do microglia normally act to mitigate neurodegeneration in ALS/FTLD? To what extent do cellular signaling pathways mediate non-cell autonomous communications between distinct central nervous system (CNS) cell types during disease? Is it possible to therapeutically target specific cell types in the CNS?

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

“…As current knowledge regarding intrinsic properties of MSNs does not adequately explain their selective vulnerability in HD, there is great interest in non-cell-autonomous and circuit-based pathogenic mechanisms in HD, including the role of non-neuronal cells. This is similar to the thought processes for other neurodegenerative disorders, e.g., amyotrophic lateral sclerosis [116][117][118] and Parkinson's disease [119,120]. Here, we will review the proposed HD pathogenic mechanisms in the context of cell-autonomous versus noncell-autonomous etiology.…”

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

“…Notably, no evidence has been shown thus far to establish the influence of AMPK on Mfn1 in the setting of cerebral IRI. Accordingly, the goal of our study is to explore the protective effect of resveratrol in cerebral reperfusion injury and mitochondrial function and verify whether resveratrol modulates mitochondrial protection and neuronal viability via the AMPK‐Mfn1 pathways …”

“…Accordingly, the goal of our study is to explore the protective effect of resveratrol in cerebral reperfusion injury and mitochondrial function and verify whether resveratrol modulates mitochondrial protection and neuronal viability via the AMPK-Mfn1 pathways. 31,32 2 | MATERIALS AND METHODS…”

NPM-hMLF1 fusion protein suppresses defects of a Drosophila FTLD model expressing the human FUS gene

“…Clinically, the patients show behavioral/personality impairments and/or language problems 1 . Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with the progressive degeneration of both upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord 2 . ALS patients develop aggressive muscle weakness and ultimately die within 3–5 years without artificial respiration 3 .…”

“…Neuropathological evidences of FTLD are characterized by protein inclusions 1 . Although about 60 percent of FTLD patients show ubiquitin and TAR DNA-binding protein 43 kDa (TDP-43) positive inclusions, four more subtypes are also identified depending on specific protein component of inclusions (FTLD-tau, FTLD-FET, FTLD-UPS and FTLD-ni) 2 , 9 . Fused in sarcoma (FUS) is identified as a component of typical inclusions in atypical FTLD with ubiquitin-positive inclusions, neuronal intermediate filament inclusion disease and basophilic inclusion body disease, which are neuropathologically categorized as FTLD-FET 10 – 12 .…”