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Liu et al. Necroptosis and immune dysfunction in ALS

subsets are preferentially elicited in ALS has been elusive. Recently, several studies support that the programmed necrosis (necroptosis),
a new type of cell death, is present in ALS. Because necroptosis results in the release of pro-inflammatory stimuli, we speculate that
initial motoneuron (MN) necroptosis may be the cause of abnormal immune responses in the development of ALS, and subsequently,
inflammation/immune response serve as an amplifier to cause more MN death. Here, the authors reviewed recent studies concerning
the type of MN death, the inflammation/immune responses and the research strategies for ALS. With the available evidences from the
literature, the authors present a hypothesized working model to indicate the possible connections among necroptosis, immune responses
and MN death in the development of ALS and suggest the future studies for searching the potential therapy for ALS.

AMYOTROPHIC LATERAL SCLEROSIS AND involved in MN death in ALS. [15,16]
RESEARCH MODEL
NECROPTOSIS AND ITS IMPLICATIONS IN
Amyotrophic lateral sclerosis (ALS) is a fatal ALS
motor neuron (motoneuron, MN) disease affecting
approximately 30,000 people in the United States Apoptosis is a well defined type of programmed cell
and 70,000 people worldwide. Clinically, ALS death with the involvement of caspase activation. MN
[1]
attacks MNs in the spinal cord, brain stem, and apoptosis has been considered as the primary cell
motor cortex, resulting in a loss of muscle tone, death in ALS. Necroptosis is one novel type of cell
[2]
generalized weakness, spasticity, paralysis, and death and it is also a type of programmed cell death but
consequent fatality. The etiology of ALS is not fully independent of caspase activation. It is stimulated by
understood, but genetic analysis has led to the TNF and related inflammatory factors such as TRAIL,
identification of approximately 30 gene mutations. FasL and ligands for TLRs. [17-20] Activated Caspase-8
[3]
The common gene mutations include Cu/Zn induces apoptosis and simultaneously represses
superoxide dismutase 1 (mSOD1), TDP-43, [5,6] necroptosis by cleaving RIP1 and RIP3. [21,22] Inhibition
[4]
repeat expansion of C9orf72 gene, [7,8] and many other of Caspase-8 can convert apoptosis to RIP1/RIP3-
mutations. The proposed pathogenic mechanisms mediated necroptosis. [23,24] Necroptosis is considered
[3]
include protein aggregation and toxicity, abnormal a pathologic form of cell death which is involved
RNA processing, glutamate-mediated excitotoxicity, in viral infection, ischemia and reperfusion injury,
and neuroinflammation. [1,3] mSOD1 is the first liver fibrosis and neurodegenerative diseases.
[25]
identified gene mutation in familial ALS (present in Necroptosis can be inhibited by the blocking RIP1/
20% of fALS); animal models have been established RIP3 interaction using a small molecule inhibitor
[9]
for this specific variant. SOD1 G93A mice carry the of RIP1 kinase, Necrostatin-1 (Nec1) or genetic
human mutant SOD1 G93A gene and demonstrate an deletion of RIP3. Rip3 mice develop and grow
-/-
ALS-like disease course. These mice are currently normally but are resistant to virus-mediated cellular
the most widely used animal model to examine the necrosis, ethanol-induced liver injury, and
[27]
[26]
behavioral, cellular, and molecular aspects of ALS. ischemia-reperfusion injury. Recent studies have
[28]
demonstrated that necroptosis in the nervous system
MN DEATH TYPES IN ALS is involved in a variety of neurological disorders, such
as multiple sclerosis (MS), traumatic brain injury, [30]
[29]
The pathological hallmark of ALS is progressive loss and cerebrovascular disease. [31] Re et al. first
[32]
of MN and motor function. The study for MN death and revealed that MN necroptosis also occurs in ALS. MN
underlying mechanisms has been the major focus of could be induced to undergo necroptosis by astrocytes
ALS research in the past decades. Due to the limited with mutant SOD1 G93A or astrocytes from ALS patients.
availability for human specimen from living ALS Because intracellular components released during
patients, most of our knowledge regarding MN death necroptosis stimulate inflammation and immune
in ALS has been derived from ALS animal model. The responses, it is thought that necroptosis contributes
previously defined cell death types in ALS include to the development/progression of neurodegenerative
apoptosis, autophagy, and necrosis. Apoptosis has diseases. Recently, Cirulli et al. compared the
[33]
been considered the main type of cell death for a long whole exome sequences between ALS and control,
time. [10-13] In the past decade, several new types of and found that the non-canonical IκB kinase family
cell death have been defined and characterized: such TANK-binding kinase 1 (TBK1) was a gene associated
as parthanatos, inflammasome (NLRP3)-mediated with ALS by interacting with ALS-related proteins,
pyroptosis, ferroptosis, pyronecrosis, mitochondrial optineurin (OPTN) and p62. Furthermore, Ito et al.
[34]
permeability transition-dependent necrosis. As recently demonstrated that OPTN inhibited dysmyelination and
reviewed by Morrice et al., accumulating evidence axonal degeneration through suppressing receptor-
[14]
indicates that multiple types of cell death may be interacting kinase 1 (RIPK1) and the downstream
110 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ June 16, 2017