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Page 6 of 13 Li et al. Ageing Neur Dis 2022;2:12 https://dx.doi.org/10.20517/and.2022.14

NHP models of ALS
ALS is a rare and fatal neurodegenerative disease caused by progressive loss of motor neurons in the brain
[106]
and spinal cord, leading to muscular atrophy and movement disorder . The prevalence of ALS is around 6
cases per 100,000, with a preference for elderly Caucasians . Similar to AD and PD, most ALS patients are
[107]
sporadic, and about 5%-10% of cases are caused by gene mutations. Mutations in the genes encoding TAR
DNA-binding protein 43 (TDP-43), superoxide dismutase 1 (SOD1), fused in sarcoma (FUS), and
C9ORF72 can result in ALS [108,109] . TDP-43 is a nuclear protein that is involved in a variety of cellular
functions, including gene transcription, RNA processing, and protein homeostasis [110,111] . In addition to ALS,
TDP-43 mutation is also associated with frontotemporal lobar degeneration (FTLD), as well as other
neurological disorders and pathological conditions. Of the pathological changes in these diseases,
cytoplastic TDP-43 accumulation is the common hallmark [112,113] . Normally, TDP-43 is located in the nuclei
but redistributed in the cytoplasm under pathological conditions. Mislocation of TDP-43 in the cytoplasm
[114]
could lead to loss of function in the nuclei and toxic function in the cytoplasm .
Several transgenic mouse models have been established to investigate ALS pathogenesis [115-117] , but most fail
to recapitulate the cytoplasmic mislocation of TDP-43 [114,118] . This phenomenon thus encourages the
establishment of new ALS animal models using large animals. A TDP-43 transgenic pig model created by
[115]
expressing mutant TDP-43 in fertilized eggs displayed the cytoplasmic distribution of TDP-43 . In
addition, a macaque monkey model, which was generated by stereotaxic delivery of a viral vector expressing
mutant TDP-43 into the cortex and substantia nigra, showed the cytoplasmic distribution of mutant TDP-
43, which is in contrast to the nuclear distribution of the same transgenic mutant TDP-43 in the mouse
[119]
brain . This finding is consistent with the previous report that exogenous mutant TDP-43 is distributed in
the neuronal cytoplasm in the monkey spinal cord . Thus, TDP-43-mediated neuronal pathology is
[120]
apparently dependent on species-specific factors. In support of this, primate-specific caspase-4 is found to
be responsible for the cleavage of mutant TDP-43 and its cytoplasmic accumulation . Comparing mouse
[119]
and monkey models of ALS also highlights the importance of using non-human primates to investigate
NDs.

NHP models of HD
HD is an autosomal dominant neurodegenerative disease with full penetration, as well as a rare inherited
monogenic disease with varied prevalence across the world. The Asian population has the lowest incidence,
while Western countries have a much higher prevalence. HD is pathogenically caused by CAG repeat
expansion (> 36 CAGs) in exon 1 of the HD gene, which is translated to the polyglutamine (polyQ) repeat
in the protein huntingtin (HTT) [121,122] . The polyQ expansion renders HTT to misfold and aggregate in the
patient’s brain, resulting in the preferential loss of the medium spiny neurons in the striatum and extensive
neurodegeneration in various brain regions as the disease progresses . Clinically, HD is characterized by
[122]
involuntary movement, called chorea. This symptom usually appears in middle life, and disease onset,
progression, and severity correlate with polyQ number. Currently, there is no effective therapy available for
[122]
HD .
Dozens of HD rodent models carrying various lengths of CAG repeats have been generated. However, none
of them can mimic overt progressive striatal neuron death [123,124] . The transgenic HD monkey model is the
first gene-modified monkey disease model , created by lentivirus injection into fertilized embryos.
[125]
Lentivirus mediates transgene insertion into the host genome at random sites with uncontrollable copy
numbers such that the transgenic HD monkey model generated by this protocol displayed overt
[126]
phenotypic heterogeneity. Among the first transgenic HD monkeys, animals with 84 CAG repeats showed
severe phenotype at the early postnatal stage, while mice carrying the same length of CAG repeats merely
displayed subtle symptoms [123,125] . However, lentivirus-mediated transgene expression is germline