Among the most distinct clinical symptoms of Prion diseases, motor impairment is the commonest at the different stages of disease development. The symptom resembles clinical features of motor neuron diseases where both or either of Upper motor neuron (UMN) or lower motor neuron (LMN) that arise from spine and brain innervating muscles are degenerated [35] . Based on the cause, severity, clinical presentation and onset of the disease, motor neuron disease (MND) are classified as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), hereditary spastic paraplegias (HSP), and progressive bulbar palsy (PBP) [36] [37] . ALS is the most common that affect both UMN and LMN neurons. Majority of ALS cases are sporadic though it can also be familial [35] . ALS is caused by a number of mutations in Cu/Zn superoxide dismutase-1 gene, ALS, cytoplasmic dynein and dynactin, D-amino acid oxidase DAO and Optineurin OPTN, Chromosome 9 open reading frame 72C9ORF72 and others [38] [39] . Mutation to superoxide dismutase1 (SOD) is the main cause of ALS next to mutation to C9ORF72 hexanucleotide repeat in the promoter region [38] [40] [41] . One of the most notable pathogenesis of this disease is glutamate-induced excitotoxicity that disrupts Ca²⁺ homeostasis to cause motor neuron death [42] [43] [44] . Apart from that, oxidative distress and axonal transport dysfunction cause neural injury through metal (Cu, iron, Zn) homeostatic disturbance [33] [45] [46] . BCL2-mediated Apoptosis, protein aggregation and autophagy are also part of pathomechanisms of ALS disease development [47] [48] [49] . As in familial Prion diseases, ALS is autosomal dominant [50] . The other type of MDN which mostly arises in the medulla is progressive bulbar palsy. Among inheritable MDN disease, spinal muscular atrophy (SMA) is autosomal recessive that affects LMN [51] where its molecular basis is an alteration in the survival motor neuron gene [52] .

Neurons of the spinal cord, brain stem, cerebellum, cerebral cortex, and basal ganglia are most affected by MND [53] [54] . Like in Prion diseases, histological studies revealed that there is also vastrogliosis [55] and microglial activation in MND [56] . Moreover, spongiosis-microvaculation is frequently documented in frontal and temporal cortices particularly in FTLD [57] . Progressive skeletal muscle weakness, wasting, fatigability, the difficulty of movement and gait disturbance, extrapyramidal diseases, tremor, atrophy, the difficulty of swallowing and other emotional disorders like anxiety, depression, excitability, dementia, and insomnia are all implicated in the majority of MND [58] [59] [60] .

As indicated above, the function of Prion is studied in relation to loss or gain of functions. In some, in in-vivo studies the knocking out/knocking down of genes or challenging Prion expression had little to no effect on the normal cellular function and/or brings no known disease phenotype [30] [61] . As a result, its biological function may be through proteins that it interacts with under the normal physiologic conditions.

Prion protein is implicated in several signaling pathways having a wide range of functions from cell differentiation [30] [62] [63] to apoptosis [64] [65] [66] . Prion protein forms interaction network with a wide variety of proteins intracellularly (Figure 1, Figure 2). Findings showed that proteins such as Stress induced phosphoprotein 1 (STIP1) [67] , Heat Shock Protein A4 (HSPA4) Clustrin (CLU) [68] , Heat shock protein family A (HSPA5) [69] , Argonaute-1 (AGO1) [70] , BCL2 Associated Athanogene 6 BAG6 [71] , and N-myc and STAT interactor (NML) are the most characterized interactomes of Prion [72] - [79] . B-Cell lymphoma 2 (BCL2) [80] [81] , Smith-Magenis syndrome chromosome region, candidate 8 (SMCR8), Proteasome subunit alpha 3 (PSMA3), Copper chaperone for superoxide dismutase (CCS) [82] , Amyloid beta precursor protein (APP) [83] [84] , Amyloid Precursor-Like Protein (1APLP1/2) [85] , WD repeat domain (5WDR5), Homeobox (A1HOXA1) [86] , and Catalase (CAT) [87] are identified to interact with Prion with a variety of cellular function. CCS and CAT are especially involved in oxidative stress [88] . BAG6, PSMA3, and SMCR8 are involved in proteolytic degradation of misfolded protein and autophagy. Heat shock protein family A44 and HSPA5 are chaperones that are involved in the folding and refolding of misfolded proteins in response to cellular stress [89] . BCL2, NML, and CLU, are mostly known for their role in either pro or anti-apoptosis activities [90] [91] . Copper chaperone for superoxide dismutase, CAT, HSPA4, SMCR8, Cone-rod homeobox (CRX), N-myc and STAT interactor (NMI), and

Ubiquitin C (UBC) [79] are common proteins that interact with Prion, SOD1, and C9ORF72. Similarly, Adenylate kinase 2 AK2, HSPA5, HSPA2 [78] , HSPH1, SOD2 [73] are especially known to interact with SOD1.

Considering the presumable and potential interaction between Prion and SOD in disease pathogenesis, it is worth to take into account the interplay between Prion and SOD1 through their interacting proteins which are common for both. The expression of SOD is somehow influenced by the level of PrP^c [92] . In another way, the loss of SOD1 up-regulating property of Prion would rather exacerbate oxidative stress which results in cell death. However, there are reports that show PrP^c having no SOD activity whatsoever [93] [94] . If the loss of SOD1 upregulating function of the Prion is indeed the cause for SOD1 dysfunction, then abrupt mitochondria-based oxidative stress and cell death would be expected.

Both Prion and SOD1 have a role in metal regulation and homeostasis [94] [95] [96] . Conversions of cellular Prion to scrapie form cause derangement of Ca²⁺ homeostasis [97] . Further Ca²⁺ homeostatic imbalance continues to occur when the L-type voltage-sensitive Ca²⁺ channel is affected by oxidative stress. As part of the signaling process that Prion plays, infective form of Prion is assumed to disrupt Ca-activated K current [98] [99] . The sum total effects of electron imbalance could be the cause of impaired neural excitability which leads to motor impairment.

In some studies, Prion peptides are documented to cause down-regulation of HSPA5 expression. The same phenomenon can be extrapolated for misfolded protein to downregulate known chaperons [100] . Likewise, impaired chaperons could also lose their protective effect of firing signal under stressful condition [101] . That often could accompany with endoplasmic reticulum stress-associated cell death [102] . By the same mechanism, down-regulation of HSPA5 may increase accumulation of misfolded SOD1 leading to MND. Thus, it might be possible to conclude HSPA5 regulation in both diseases is a key phenomenon in motor dysfunction development [103] .

Experimental evidence confirms CCS maintains SOD [104] . The Cu served to SOD is taken up by the Prion. Loss of Cu uptake function disturbs normal function of CCS [30] . As a result, SOD is unable to perform its normal cellular functions. Accumulation of Cu in cytosol causes up-regulation of cellular Prion under physiologic conditions [96] . Misfolded Prion seed, according to Refolding Hypothesis, recruits cellular Prions as their own substrate [105] . It is possible to predict that upon up-regulation of Prion by Cu might further potentiate misfolded aggregate to form amyloid. In addition to this effect, either physical axonal transport blockage and/or an increase in oxidative stress kills neurons. Studies showed extracellular Cu also control expression and turnover of PrP^c in neurons. The transport of Prion from neuron to astrocyte is somehow mediated by extracellular Cu [96] . In turn, PrP^c participates in Cu transport from neuron to astrocyte. This complementary function protects the cell from Cu toxicity [106] . When PrP^c loses this protective function, the concentration of Cu might increase both in extracellular space, astrocytes and other neurons. An invitro study also showed Cu to enhance renaturation and stabilization of PrPSc, and again further boost its resistance and infectivity [107] .

PrPSc cause downregulation of PSMA3. In this case, there might be the bulk removal of cells [108] . Overexpressed PSMA3 could fatigue its own normal function of removing misfolded proteins [109] . Such condition brings in a toxic gain function of Prion and loss of protective function of SOD causing motor neuron death [30] [110] [111] [112] [113] . CAT is another very important protein in processing reactive oxygen species together with SOD [114] . Protein and lipid oxidation increase in Prion knocked out and catalase deficient model animals [111] [115] . The synergetic effect of a decrease in catalytic activity and increased oxidation could result in neural death.

Under the physiologic condition, Clusterin is a ligand for PrP^c [68] . In Prion diseased sample, Clusterin is believed to form an aggregate with misfolded Prion [116] . That might suggest a structural change which challenges the interaction of Clusterin and Prion. As a result, removal of aggregates might be boldly jeopardized. Aggregates and precipitations are the prominent cause of cell death. Proteins in UPS and autophagy are the other molecular phenomenon that is frequently mentioned in trafficking and maintaining the normal cellular function of Prion [101] . These systems are important machineries playing the role of removing misfolded proteins. Dysfunctional proteins, misfolded proteins, are believed to possess structures that potentially challenge interactions with chaperones for degradation. Ub and NMI are among the many proteins that are displayed in UPS and autophagy of neurodegenerative disease [101] [116] . Those proteins are documented to interact with Prion and SOD. AGO is an interesting protein with a critical function in the regulation of miRNA. Ago regulate protein translation through its catalytic action by forming a complex called RISC with miRNA [117] [118] . It is also an interactome to Prion [119] and potentially to SOD. Any abnormal interaction with dysfunctional proteins can potentially subvert normal function of AGO and threaten cell survival. And again, the loss of interaction with those key proteins might be the reason for the development of the disease (Figure 3).