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?

Fig. 1

A model of neuron–microglia interplay in disease progression. In a healthy individual, all cells within the CNS are equipped with a myriad of functionalities to maintain optimal homeostasis as well as an ability to respond to acute insults. This process is regulated in both an autonomous and non-cell autonomous manner. A healthy neuron undergoes normal mitochondrial fission/fusion and elimination of damaged mitochondria, efficient axonal transport, and RNA metabolism. In healthy microglia, key functionalities actively maintain CNS homeostasis by directly interacting with the extracellular space via both phagocytosis- and lysosomal-mediated flux. During the aging process, neurons can become damaged due to an ALS causal mutation, sustained head trauma, environmental stresses, or some combination thereof; in ALS, this leads to motor neuron dysfunction (Hit 1). This may lead to alterations in neuronal proteostasis and/or basic cellular functions, e.g., in mitochondria biogenesis/dynamic, axonal transport, or RNA metabolism. Under such conditions, the genetics as well as the mechanistic data indicate that microglial function also becomes impaired (Hit 2). This microglial impairment is manifested via dysfunction in autophagy, phagocytosis and/or other homeostatic cellular pathways in these cells, resulting in a shift in their secretory/inflammatory profiles. Thus, it is these multi-cell and multi-pathway failures (Hit 1 + Hit 2) that we hypothesize lead to the initiation of ALS/FTLD. As other cells (e.g., astrocytes, oligodendrocytes) in the affected micro-environment respond, they too become functionally aberrant in a similar fashion, causing further damage and progressive degeneration (Hits 1/2 + Hits 3/4)

Fig. 2

C9ORF72 associates with multiple cellular pathways relevant to ALS/FTLD. A schematic representation of the genomic structure of C9ORF72, showing the location of the (GGGGCC) hexanucleotide expansion in the intronic region between two alternative non-coding first exons. This expansion leads to three observable phenotypes. One is C9ORF72 loss-of-function leading to a blockade of lysosomal function and an alteration in immune function. Based on the RNA expression profile of this gene, this haploinsufficiency phenotype primarily affects microglia in the CNS. In addition, there are two other phenotypes observed in both C9ORF72 ALS/FTLD patients and in animal models of the disease. The (GGGGCC) hexanucleotide expansion leads to the formation on RNA foci, which results in the mislocalization and sequestration of RNA-binding proteins causing nuclear and cellular dysfunction. Finally, through repeat-associated non-ATG-dependent translation, (GGGGCC) hexanucleotide repeats can produce five different types of dipeptide repeat sequences, depending on the direction (sense and anti-sense) and frame of translation (GA, GR, GP, PR, and PA). These aberrant species lead to protein aggregation, toxicity, lysosomal blockade, and overall cellular dysfunction. This most common genetic cause of ALS/FTLD illustrates the potential contribution of disruptions to multiple cellular pathways in various cell types to disease