TABLE 1.
Examples of preclinical therapeutic strategies targeting lysosomal function.
| Strategy | Target | Agent | Application route | Main effect | PD model | References |
| Chaperone | GCase | Isofagomine | Oral | Improved motor and non-motor function, less neuroinflammation, increased aSyn clearance, fewer olfactory deficits | SNCA transgenic mice (Thy1-aSyn, line 61) | Richter et al., 2014 |
| Chaperone | GCase | Ambroxol | Oral | Increased GCase activity, reduction of aSyn levels | SNCA transgenic mice with absence of mouse snca | Migdalska-Richards et al., 2016 |
| Chaperone | GCase | Ambroxol | Oral | Improved motor function, dopaminergic system recovery, reduction of aSyn pathology | 6-OHDA rat model | Mishra et al., 2018 |
| Chaperone | GCase | Ambroxol | Oral | Increased GCase activity | Healthy non-human primates | Migdalska-Richards et al., 2017 |
| Small molecule | GCS | GZ667161 | Oral | Reduction of glucosylceramide levels, amelioration of memory deficit, reduction of hippocampal aSyn aggregates | GbaD409V/D409V and A53T–SNCA mice | Sardi et al., 2017 |
| Viral vector | TFEB | AAV-TFEB | Intracerebral | Prevention of behavioral impairment, protection of nigral DA neurons | AAV-aSyn rat model | Decressac et al., 2013 |
| Viral vector | Beclin 1 | AAV-Beclin 1 | Intracerebral | Prevention of behavioral impairment, protection of nigral DA neurons | AAV-aSyn rat model | Decressac et al., 2013 |
| Viral vector | LAMP-2A | AAV-LAMP-2A | Intracerebral | Amelioration of dopaminergic neurodegeneration, reduction in total aSyn levels | AAV-aSyn rat model | Xilouri et al., 2013 |
| Nanoparticles | Lysosome | Acidic nanoparticles | Intracerebral | Restored lysosomal pH and lysosomal function (all models), inhibited dopaminergic cell death (MPTP-treated mice) | MPP+-treated cells, ATP13A2 mutant fibroblasts, and MPTP-treated mice | Bourdenx et al., 2016 |
| Nanoemulsions | Lysosome | Acidic nanoemulsions | Intracerebral, retro-orbital injections | Restored lysosomal pH and lysosomal function (in vitro), biodistribution into the SNc and VTA (WT mice) | ATP13A2- mutant M17 cells, and WT mice | Prevot et al., 2018 |
AAV, adeno-associated virus; aSyn, alpha synuclein; DA, dopamine; GCase, β-glucosidase; GCS, glucosylceramide synthase; LAMP, lysosomal-associated membrane protein; MPP+, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA, 6-hydroxydopamine; TFEB, transcription factor EB; VTA, ventral tegmental area.