Protein quality control is essential for maintenance of a healthy and functional proteome that can attend the multiplicity of cellular functions. Failure of the systems that contribute to protein homeostasis, the so called proteostasis networks, have been identified in the pathogenesis of multiple neurodegenerative disorders and demonstrated to contribute to disease onset and progression. We are interested in autophagy, one of the components of the proteostasis network, and in the interplay of wo selective types of autophagy, chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI), with neurodegeneration. We have recently found that pathogenic proteins involved in common neurodegenerative conditions such as tauopathies or Parkinson’s disease, can exert a toxic effect in both types of selective types of autophagy compromising their functioning. We have now used mouse models with compromised CMA that support increased propagation of proteins such as tau and alpha-synuclein and an exacerbation of disease phenotype with aging. Conversely, genetic or chemical upregulation of CMA in this context of proteotoxicity slow down disease progression by facilitating effective intracellular removal of pathogenic proteins. Our findings highlight CMA and eMI as potential novel therapeutic targets against neurodegeneration.